Review Article
PEDIATRIC HEMATOLOGY A N D ONCOLOGY IN NORWAY: A Brief Historical Review
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Martin Seip, MD 0 Department of Pediatrics, The National Hospital, Rikshospitalet, 0027 Oslo 1, Norway Before World War I1 no real subspecialization occurred in NorweEian pediatrics. In the earh 1950s hematology and oncology were adopted as fields of special interest by a f e w Norwegian pediatricians. Gradually an increasiny expansion hns taken place, particularly in pediatric oncology, in parallel with the great advances in cancer treatment. KEY WORDS: Norway, pediatric hematology, pediatric oncology
PEDIATRIC HEMATOLOGY Before World War I1 a number of papers with topics from pediatric hematology were published. The most important were written by Leif Salomonsen (1989- 1972), who subsequently became professor and chairman of the Department of Pediatrics at the National Hospital in Oslo. In 1939 he published a monograph Morbus Hemorrhagicus Neonatorum. Hypofirothrombinemia Neonatorum [Bleeding Disorder of Newborns. Hypoprothrombinemia in Newborns]' with a detailed description of 66 cases. This appeared only few years after Henrik Dam had detected and isolated vitamin The first Norwegian pediatrician to adopt hematology as his main field of interest was Martin Seip (1921-), who also worked in the Department of Pediatrics at the National Hospital (chairman 1968-1988). This interest was awakened while Seip was working with Paul A. Owren in Oslo, and later as a research fellow with Louis K. Diamond in Boston. Seip published his thesis Reticulocyte Studies in 1953,* describing the liberation of young red blood cells from the bone marrow under normal conditions, the normal reticulocyte pool in the bone marrow, and the stage at which the reticulocytes enter the circulation. In this monograph questions regarding regulation of erythrocyte production were also discussed. Subsequent publications contributed to our knowledge on erythropoiesis and reticulocyte levels in the first week of life, and in premature infants during the first trirne~ter.~ This work resulted from a collaboration between Seip and Sverre Halvorsen (1925-). K.'I3
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In 1959 and 1960 Olga Imerslund (1907-1987) described the disease which now bears her name,6 a hereditary juvenile pernicious anemia with normal ventricular acidity and intrinsic factor, and frequently proteinuria (Imerslund anemia, Imerslund-Grasbeck anemia). She was later, in collaboration with Bjdrnstad, able to show that this disease is due to a selective malabsorption of vitamin B,,.7 The Department of Pediatric Research at the National Hospital in Oslo was started on a small scale in 1959 at the initiative of Martin Seip. At that time it seemed appropriate to start the research activities with hematologic problems. Two main subjects were chosen: the mechanism of erythropoietic regulation and the iron requirements in infancy.
Iron and Folate Requirements in Infancy During the late 1950s moderate iron deficiency anemia was very common in Norwegian infants and toddlers. In 1957 Seip’ introduced iron-enriched baby cereals in Norway in order to improve this situation. The amount of iron added to the cereals was based on the well-known study by Peter Johan Moe (1923-) on Iron Requirements in Infancy, and Normal Blood Values during the First Years of Liji, published in 1965.’ Baby cereals with varying iron content were used in extensive trials under controlled conditions in groups of healthy infants. The minimum daily iron requirement necessary to achieve optimal hemoglobin levels under these conditions was 10 mg for infants 5 to 12 months old. Another extensive and important research project along a similar line has been carried out by Johan Ek (1936-) on the folic acid status of infants on breast feeding and formula feeding, and folic acid requirements in infancy. Recommendations have been made for the enrichment of infant formulas with folic acid to avoid deficiency. The relationship between folic acid levels in mother and newborn child was also elucidated. Ek’s thesis, Folate Studies during Pregnancy, Lactation and Infancy, was published in 1986.lo
Regulation of Red Cell Production The mechanism of erythropoietic regulation has been studied extensively since 1959, initially under the supervision of Seip and Halvorsen. Halvorsen gradually took over the responsibility for this project, which was transferred to Ullevd Hospital in 1975 when Halvorsen was appointed chairman of the Department of Pediatrics there. The possible role of the central nervous system in regulation of erythropoiesis was investigated in collaboration with the Institute of Neurophysiology, University of Oslo, and was the subject of Halvorsen’s doctoral thesis in
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1966." In studies of rabbits it was found that erythropoiesis could be enhanced by electrical stimulation of a special region in the posterior hypothalamus. The role of the central nervous system in regulation of erythropoiesis may be underestimated today. Per H. Finne (1931-) was the first investigator to demonstrate erythropoietin in the urine of normal persons, thus proving convincingly the role of erythropoietin in the regulation of red cell production even under normal, basal conditions. Finne, in collaboration with Halvorsen, studied erythropoietin levels in the neonatal period and in the amniotic fluid in normal pathologic pregnancies, showing that erythropoietin is produced by the fetus. These studies have contributed substantially to our understanding of fetal and neonatal erythropoiesis. Finne published his thesis, Studies on Erythropoietin, in 1967.'* An erythropoiesis inhibiting factor was studied by Rolf Lindemann (1942-). The factor was demonstrated in plasma, urine, and erythrocytes. It is possible that this factor is of importance in the normal regulation of erythropoiesis. Lindemann's thesis Erythropoiesis Inhibiting Factor (EIF). Studies on the Urinary EIC was published in 1976.13 In 1984 Per High (1944-) published his thesis, The Early Anemia ofPrema14 turity. Studies on the Role of Iron, Oxygen Toxic& and Erythropoietin. He found a significant increase in plasma erythropoietin during the early anemia of prematurity. Halvorsen and his group have carried out important studies on the regulation of erythropoiesis in newborn mice, rats, and rabbits during their early growth period. They have shown that the "early anemia" in rabbits and mice can be prevented by parenteral iron medication. Other findings were presented in the thesis of Truls Sanengen (1949-) in 1989, Regulation .fErythropoiesis in the Neonatal Mammal during the Growth Period. l 5 The regulation of erythropoiesis in the newborn mouse and rabbit differs to some extent from that in the adult animal, as erythropoietin is not the only erythropoiesis-stimulating factor found in their plasma. It is speculated that insulin-like growth factor 1 may be another. Bilirubin Metabolism and Toxicity
In 1964 a group working with bilirubin metabolism and bilirubin toxicity was established in the Department of Pediatric Research by Jdrgen Fog (1918-1989). This work resulted in the following doctoral theses: Bilirubinutskillelsens Aktivering Hos Nyfddte [The Activation of Bilirubin Excretion in newborn^]'^ by Arne F. Bakken (1942-1990) in 1969, Albumin Binding and Toxicity of Bilirubin. The Protective Effect of Albumin on Bilirubin Toxicity and Factors Injluencing the Binding of Bilirubin to Albumin" by Dag Bratlid (1944-) in 1973,
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and Regulation of Hepatic UDP-Glucuronyltransfrase‘8 by Arnt Winsnes (1939-) in 1973. After a prolonged pause the bilirubin studies were restarted by Bratlid in 1983. The main results of these investigations are found in the thesis of Bratlid’s fellow Thor Willy Ruud Hansen (1946-), Bilirubin and Brain Toxicity. Studies on the E n t v , Localization, and Effects of Bilirubin in Rat Brain, published in 1988.” One important finding was that bilirubin inhibited synaptic activation, partly by inhibition of phosphorylation of synapsin 1,
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Thrombocytopenia in Children In 1981 Danish pediatric hematologist Jdrgen Cohn (1937-) joined the medical faculty at the University of TromsQ as professor of pediatrics. He had already defended his thesis Thrombocytopeni Hos Bdrn, en Ouersigt [Thrombocytopenia in Children, a Survey],20published in 1977. The thesis was based on a large epidemiologic study of thrombocytopenia in 433 children in Denmark.
Nordic Club for Pediatric Hematologists In the 1960s an increasing number of prominent pediatricians in the Nordic countries became interested in hematology, including Stig Sjolin and Lars Wranne in Sweden, Ruth Wegelius and Harri Nevanlinna in Finland, Torben Iversen in Denmark, and Martin Seip, Sverre Halvorsen, and Peter Johan Moe in Norway. During a meeting in Turku some of them met in Tuomas Peltonen’s sauna, and in this pleasant atmosphere decided to establish an informal Nordic Club for Pediatric Hematologists. The first meeting of this Club took place in Oslo on 1968. Thereafter meetings were arranged every year or every other year in one of the four Nordic countries on a rotation basis. Both benign hematology and leukemia were discussed. Gradually many of the club members became more and more involved in the treatment of leukemia, and somewhat later Wilms’ tumor and other solid tumors. Consequently in 1984 the Club merged with the pediatric oncologists to establish the formal Nordic Society for Pediatric Hematology and Oncology, NOPHO. Also in 1984 Jdrgen Cohn started the journal European Paediatric Haematology and Oncology, now known as Pediatric Hematology and Oncology.
European Society for Paediatric Haematology and Immunology During a meeting of the European Society for Paediatric Research (ESPR) in Interlaken in 1969, a special session for pediatric hematology was arranged. A decision was made to establish the European Society for Paediat-
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ric Haematology and Immunology (ESPHI). Active in this process were Walter Hitzig, Zurich; K.-H. Schafer, Hamburg; Stig Sjolin, Uppsala; and Martin Seip in Oslo; among others. The first president of the society was Stig Sjolin, and the first regular meeting was held in Stockholm in 1970. Seip has served as president of this society during two periods, 1970-1972 and 19771979.
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PEDIATRIC ONCOLOGY Modern pediatric oncology started in the late 1940s at the Children's Medical Center in Boston with the demonstration that remission could be achieved in some children with acute lymphocytic leukemia (ALL) by the use of folic acid antagonist, aminopterin.*' In Norway, systematic treatment of childhood leukemia with cytostatics was introduced by Martin Seip in Oslo in 1954, after his study period in Boston. In the beginning corticosteroids and aminopterin were the drugs used; soon 6-mercaptopurin, methotrexate, and vincristine were also used. At that time leukemia was thought to be incurable, but in the 1960s we gradually learned that with more intensive treatment cure was indeed possible. The first patients who were cured in the Oslo material developed leukemia in 1968. From the middle of the 1960s Peter Johan Moe, working at the time in Bergen, devoted much of his time to pediatric oncology, at first leukemia, then solid tumors. He later introduced modern pediatric oncology in Tromsd in 1972, and in Trondheim in 1978. In 1972, at Roswell Park Memorial Institute in Buffalo, a new approach to the chemotherapy of childhood ALL was introduced. Infusions of methotrexate 500 mg/m2 were given intravenously, followed by leucovorin rescue, as an important element in the consolidation phase of the treatment. Promising results were reported." As the first in Europe, Moe included this as part of the treatment protocol in Norway in 1975. This principle (later called intermediate dose methotrexate or IDM) was soon adopted by Seip in Oslo and Finne in Bergen. A National Norwegian Study using IDM was undertaken from 1975 to 1980, with remarkably good results for that time.23 Moe has with great enthusiasm advocated IDM and later high dose methotrexate (HDM), particularly in ALL. One advantage of IDM and HDM in the ALL protocol is that, in combination with intraspinal methotrexate injections, prophylactic irradiation of the central nervous system with its side effects can be avoided, a fact repeatedly stressed by Moe. Methotrexate metabolism and pharmacokinetics have been studied in detail in Trondheim by a visiting researcher from Hungary, Joseph Borsi. His main findings have been published in his 1988 thesis New Aspects ofthe Clinical
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Pharmacokinetics of Methotrexate. Studies in Children with Acute Lymphoblastic Leuke24 mia. In 1973, Moe started to register all new cases of leukemia and malignant lymphoma in Norwegian children. As of January 1, 1981, the Norwegian registry became part of a common Nordic registry in Uppsala, directed by Goran Gustafsson. Solid malignant tumors have been registered at the National Hospital in Oslo since 1980, from 1985 as part of a common Nordic registry in the Cancer Registry in Oslo, supervised by FrQydis Langmark. Moe and his coworkers in Trondheim have also performed a large study of the long-term results of leukemia patients in the Nordic countries. The results are presented in the thesis of Randi Nygaard (1945-) in 1991, Long-term Suruiual in Childhood Leukemia. Relapses and Late Effects After Completed Therapj,25 Two other pediatricians working at the University of Trondheim have written their theses on topics from hematology and oncology: BjQrn Magne Eggen (1950-) Studies in Cytotoxicity in Human Adherent Mononuclear Blood Cells in 1984,26and Rigmor Austgulen (1949-) Tumor Necrosis Factor: A Monocyte Derived Regulator of Cellular Growth in 1988.2’ In Oslo, Seip continued his involvement in ALL treatment until his retirement in 1988. From about 1970 Sverre 0. Lie (1938-) gradually took over the responsibility for treatment of acute myleoblastic leukemia (AML) and the solid tumors. The tumors have been treated in close collaboration with pediatric surgeons Ola Knutrud (1919-) and Thomas Monclair (1942-). Lie has enthusiastically devoted much of his time to pediatric oncology. One of his main fields of interest is the treatment of AML. In this field he is the coordinator of a Nordic treatment protocol which involves a tough cytostatic regimen combined with high doses of vitamin A. He is also engaged in an international neuroblastoma project. Lie has also established a unit for cell culture studies in the Department of Pediatric Research. Here, in collaboration with IngebjQrg Storm-Mathisen (1940-), Jon Helgestad (1950-) wrote his thesis In Vitro Hemopoiesis. A Study of Inhibitory Activities Under Different Culture Conditions, published in 1990.** An exciting research program has been conducted in recent years in a collaboration between Karl-Ludvig Reichelt (1933-) and coworkers in the Department of Pediatric Research, and Olav Hilmar Iversen (1923-), Kjell Elgjo (1933-), and coworkers in the Institute of Pathology of the National Hospital. Reichelt has isolated and characterized a “family” of small peptides that are tissue specific inhibitors of mitoses. Several of these have been synthesized. Their biologic activities have been studied in the Institute of Pathology. So far peptides from epidermis, colon, liver, and small intestine have been isolated and synthetized. The colonic peptide has been described by 0yvind Skraastad in 1989 in his thesis Isolation and Biological Properties of an Endogenous Inhibitor of Colonic Epithelial Cell Proliferation. 29
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In Bergen, Finn Wesenberg (1946-) has headed the pediatric oncology work since 1984. His thesis, published in 1981, was titled IgG, Other Proteins and Fcy Receptors Associated with Human Malignant Tissues. 30
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Nordic Society for Pediatric Hematology and Oncology (NOPHO)
In 1980 Swedish pediatric oncologists arranged a Nordic meeting in Orenas. The aim was to further Nordic cooperation in the field. In 1981 the Nordic Pediatric Leukemia Group was established, and a close collaboration on ALL treatment was begun. In 1984 NOPHO was formally established at a meeting in Reykjavik. The Nordic Club for Pediatric Hematologists was included in NOPHO. During the first four years Henrik Hertz from Denmark acted as Secretary General of NOPHO. Since 1988 Sverre 0. Lie has led the organization. Norwegian pediatric oncologists have actively participated in the Nordic collaboration in NOPHO, which has been stimulating and rewarding. The cooperative studies on leukemia treatment have been particularly important. A good medulloblastoma project has been carried out and several other projects are under way. SociCtC lnternationale d’Oncologie P4diatrique (SIOP)
SIOP, formally established in 1969, has gained an important role, and Norwegian pediatric oncologists have been stimulated by participating in SIOP activities. The first really dramatic progress in the treatment of solid tumors in children occurred in Wilms’ tumor, with a combination of surgery and cytostatic drugs. SIOP had several multicenter studies of Wilms’ tumor. From the Norwegian side, Moe and Lie have been the most active members of SIOP. Moe arranged a successful SIOP meeting in Trondheim in 1988. Lie has been member of the Board since 1987. He has convinced the Norwegian pharmaceutical company Nycomed to support the Society with an annual amount of $10,000 for 5 years. The amount is awarded by SIOP for particularly good papers and is known as the Nycomed prize. Support from Norwegian Cancer Societies
Without the generous support of cancer societies that have merged in the Norwegian Cancer Society, Norwegian pediatric oncology would be in poor shape. The Norwegian Cancer Society founded the first full-time position in pediatric oncology in Norway in 1984 (Ingebjdrg Storm-Mathisen), and sub-
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sequently founded similar positions in Bergen, Trondheim, and TromsB. It pays salaries for many other professionals (nurses, psychologists) in our units for pediatric oncology in Oslo, Bergen, Trondheim, and TromsB. The society also supports several research projects and has a subdivision for pediatric patients and their families. The Norwegian Cancer Society deserves our most sincere gratitude.
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REFERENCES 1. Salomonsen L. Morbus Hemorrhagicus neonatorum. Hypoprothrombinemia neonatorum [Bleeding disorder of hypoprothrombinemia in newborns]. Acta Paediatr. 1939;27(Suppl 41): 1-120. 2. Dam H . Cholesterinstoffwechsel in Hiihnereiern und in Hiinchen [Cholesterol metabolism in hen’s eggs and young hens]. Biochem Z. 1929;215:475-492. 3 . Dam H , Gerger A, Glavind J et al. Isolierung des Vitamins K in hochgereiniger Form [Isolation of vitamin K in highly purified form]. Helv Chim Acta. 1939;22:310-313. 4. Seip M . Reticulocyte studies. Acta Med Scand. 1953;146(Suppl 282):l-164. 5. Seip M, Halvorsen S. Erythrocyte production and iron stores in premature infants during the first months of life. The anemia of prematurity-etiology, pathogenesis, iron requirement. Acta Paediatr Scand. 1956;45:600-617. 6 . Imerslund 0. Idiopathic chronic megaloblastic anemia in children. Acta Paediatr Scand. 1960;49 (Suppl 1 19): 1-1 15. 7 . Imerslund 0, BjQrnstad P. Familial vitamin B,, malabsorption. Acta Haemat. 1963;30:1-7. 8. Seip M , Amlie R . Nye prinsipper i spebarnsernaeringen. Tidsskr Nor Laegeforen [New principles in infant nutrition]. 1957;77:729-734, 9. Moe PJ. Iron Requirements in Injancy, and Normal Blood Values during the First Ears of Life, Oslo, Norway: University of Oslo; 1965. Thesis. 10. Ek J. Folate Studies during Pregnancy, Lactation and Injany. Oslo, Norway: University of Oslo; 1986. Thesis. 11. Halvorsen S . The Central Neruous System in Regulation ojErythropoiesis. Oslo, Norway: University of Oslo; 1966. Thesis. 12. Finne P H . Studies of Erythropoietin. Oslo, Norway: University of Oslo; 1967. Thesis. 13. Lindemann R. Erythropoiesis Inhibitins Factor (EIF). Studies on the Urinary EIE Oslo, Norway: University of Oslo; 1976. Thesis. 14. HHgi P. The E a r 4 Anemia of Prematurity. Studies on the Role of Iron, Oxygen Exicity, and Erythropoietin. Oslo, Norway: University of Oslo; 1984. Thesis. 15. Sanengen T. Regulation of Erythropoiesis in the Neonatal Mammal during the Growth Period, Oslo, Norway: University of Oslo; 1989. Thesis. 16. Bakken AF. Bilirubinutskillelsens aktiuering hos nyfddte [The Activation of Bilirubin Excretion in Newborns]. Oslo, Norway: University of Oslo; 1969. Thesis. 17. Bratlid D. Albumin Binding and Toxicity of Bilirubin. The Protective Effect ofAlbumin on Bilirubin Toxicity and Factors InJuencing the Binding of Bilirubin to Albumin. Oslo, Norway: University of Oslo; 1973. Thesis. 18. Winsnes A. Regulation of Hepatic UDP-Glucuronyltran~erase.Oslo, Norway: University of Oslo; 1973. Thesis. 19. Hansen T W R . Bilirubin and Brain Exici(y. Studies on the Entry, Localization, and Effects of Bilirubin in R a t Brain. Oslo, Norway: University of Oslo; 1988. Thesis. 20. Cohn J . Trombocytopeni hos bdm, en ouersiyt [Thrombocytopenia in Children, a Survey]. Copenhagen, Denmark: University of Copenhagen; 1977. Thesis. 21. Farber S, Diamond LK, Mercer R D et al. Temporary remissions in acute leukemia in children produced by folk acid antagonist. N EnglJMed. 1948;238:787-793. 22. Wang JJ, Freeman AI, Sinks LF. Treatment of acute lymphocytic leukemia by high-dose intravenous methotrexate. Cancer Res. 1976:36: 1441-1444.
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23. Moe PJ, Seip M , Finne P H . Intermediate dose methotrexate (IDM) in childhood acute lymphocytic leukemia in Norway. Acute Paediatr Scand. 1981;70:73-79. 24. Borsi JD. N e w Aspects of the Clinical Pharmacokinetics of Methotrexate. Studies in Children with Acute Lymphoblastic Leukemia. Trondheim, Norway: University of Trondheim; 1988. Thesis. 25. Nygaard R. Long-Term Survival in Childhood Leukemia. Relapses and Late Effects After Completed Therapy. Trondheim, Norway: University of Trondheim; 1991. Thesis. 26. Eggen BM. Studies in Cytotoxicily in Human Adherent Mononwlear Blood Cells. Trondheim, Norway: University of Trondheim; 1984. Thesis. 27. Austgulen R. Tumor Necrosis Factor: A Monocyte-Derived Regulator of Cellular Growth. Trondheim, Norway: University of Trondheim; 1988. Thesis. 28. Helgestad J. In Vitro Hemopoiesis. A Study of Inhibitory Activities Under Di&nt Culture Conditions. Oslo, Norway: University of Oslo; 1990. Thesis. 29. Skraastad 0. Isolation and Biolojical Properties of an Endogenous Inhibitor of Colonic Epithelial Cell Prolifertion. Oslo, Norway: University of Oslo; 1989. Thesis. 30. Wesenberg F. IgG, Other Proteins and Fcy Receptors Associated with Human Mal%nant Tissues. Bergen, Norway: University of Bergen; 1981. Thesis. Received April 22, 1991 Accepted April 22, 1991 Address correspondence to M. Seip.
PEDIATRIC HEMATOLOGY A N D ONCOLOGY IN NORWAY: A Brief Historical Review
Pediatr Hematol Oncol Downloaded from informahealthcare.com by McMaster University on 01/14/15 For personal use only.
Martin Seip, MD 0 Department of Pediatrics, The National Hospital, Rikshospitalet, 0027 Oslo 1, Norway Before World War I1 no real subspecialization occurred in NorweEian pediatrics. In the earh 1950s hematology and oncology were adopted as fields of special interest by a f e w Norwegian pediatricians. Gradually an increasiny expansion hns taken place, particularly in pediatric oncology, in parallel with the great advances in cancer treatment. KEY WORDS: Norway, pediatric hematology, pediatric oncology
PEDIATRIC HEMATOLOGY Before World War I1 a number of papers with topics from pediatric hematology were published. The most important were written by Leif Salomonsen (1989- 1972), who subsequently became professor and chairman of the Department of Pediatrics at the National Hospital in Oslo. In 1939 he published a monograph Morbus Hemorrhagicus Neonatorum. Hypofirothrombinemia Neonatorum [Bleeding Disorder of Newborns. Hypoprothrombinemia in Newborns]' with a detailed description of 66 cases. This appeared only few years after Henrik Dam had detected and isolated vitamin The first Norwegian pediatrician to adopt hematology as his main field of interest was Martin Seip (1921-), who also worked in the Department of Pediatrics at the National Hospital (chairman 1968-1988). This interest was awakened while Seip was working with Paul A. Owren in Oslo, and later as a research fellow with Louis K. Diamond in Boston. Seip published his thesis Reticulocyte Studies in 1953,* describing the liberation of young red blood cells from the bone marrow under normal conditions, the normal reticulocyte pool in the bone marrow, and the stage at which the reticulocytes enter the circulation. In this monograph questions regarding regulation of erythrocyte production were also discussed. Subsequent publications contributed to our knowledge on erythropoiesis and reticulocyte levels in the first week of life, and in premature infants during the first trirne~ter.~ This work resulted from a collaboration between Seip and Sverre Halvorsen (1925-). K.'I3
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In 1959 and 1960 Olga Imerslund (1907-1987) described the disease which now bears her name,6 a hereditary juvenile pernicious anemia with normal ventricular acidity and intrinsic factor, and frequently proteinuria (Imerslund anemia, Imerslund-Grasbeck anemia). She was later, in collaboration with Bjdrnstad, able to show that this disease is due to a selective malabsorption of vitamin B,,.7 The Department of Pediatric Research at the National Hospital in Oslo was started on a small scale in 1959 at the initiative of Martin Seip. At that time it seemed appropriate to start the research activities with hematologic problems. Two main subjects were chosen: the mechanism of erythropoietic regulation and the iron requirements in infancy.
Iron and Folate Requirements in Infancy During the late 1950s moderate iron deficiency anemia was very common in Norwegian infants and toddlers. In 1957 Seip’ introduced iron-enriched baby cereals in Norway in order to improve this situation. The amount of iron added to the cereals was based on the well-known study by Peter Johan Moe (1923-) on Iron Requirements in Infancy, and Normal Blood Values during the First Years of Liji, published in 1965.’ Baby cereals with varying iron content were used in extensive trials under controlled conditions in groups of healthy infants. The minimum daily iron requirement necessary to achieve optimal hemoglobin levels under these conditions was 10 mg for infants 5 to 12 months old. Another extensive and important research project along a similar line has been carried out by Johan Ek (1936-) on the folic acid status of infants on breast feeding and formula feeding, and folic acid requirements in infancy. Recommendations have been made for the enrichment of infant formulas with folic acid to avoid deficiency. The relationship between folic acid levels in mother and newborn child was also elucidated. Ek’s thesis, Folate Studies during Pregnancy, Lactation and Infancy, was published in 1986.lo
Regulation of Red Cell Production The mechanism of erythropoietic regulation has been studied extensively since 1959, initially under the supervision of Seip and Halvorsen. Halvorsen gradually took over the responsibility for this project, which was transferred to Ullevd Hospital in 1975 when Halvorsen was appointed chairman of the Department of Pediatrics there. The possible role of the central nervous system in regulation of erythropoiesis was investigated in collaboration with the Institute of Neurophysiology, University of Oslo, and was the subject of Halvorsen’s doctoral thesis in
Pediatr Hematol Oncol Downloaded from informahealthcare.com by McMaster University on 01/14/15 For personal use only.
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1966." In studies of rabbits it was found that erythropoiesis could be enhanced by electrical stimulation of a special region in the posterior hypothalamus. The role of the central nervous system in regulation of erythropoiesis may be underestimated today. Per H. Finne (1931-) was the first investigator to demonstrate erythropoietin in the urine of normal persons, thus proving convincingly the role of erythropoietin in the regulation of red cell production even under normal, basal conditions. Finne, in collaboration with Halvorsen, studied erythropoietin levels in the neonatal period and in the amniotic fluid in normal pathologic pregnancies, showing that erythropoietin is produced by the fetus. These studies have contributed substantially to our understanding of fetal and neonatal erythropoiesis. Finne published his thesis, Studies on Erythropoietin, in 1967.'* An erythropoiesis inhibiting factor was studied by Rolf Lindemann (1942-). The factor was demonstrated in plasma, urine, and erythrocytes. It is possible that this factor is of importance in the normal regulation of erythropoiesis. Lindemann's thesis Erythropoiesis Inhibiting Factor (EIF). Studies on the Urinary EIC was published in 1976.13 In 1984 Per High (1944-) published his thesis, The Early Anemia ofPrema14 turity. Studies on the Role of Iron, Oxygen Toxic& and Erythropoietin. He found a significant increase in plasma erythropoietin during the early anemia of prematurity. Halvorsen and his group have carried out important studies on the regulation of erythropoiesis in newborn mice, rats, and rabbits during their early growth period. They have shown that the "early anemia" in rabbits and mice can be prevented by parenteral iron medication. Other findings were presented in the thesis of Truls Sanengen (1949-) in 1989, Regulation .fErythropoiesis in the Neonatal Mammal during the Growth Period. l 5 The regulation of erythropoiesis in the newborn mouse and rabbit differs to some extent from that in the adult animal, as erythropoietin is not the only erythropoiesis-stimulating factor found in their plasma. It is speculated that insulin-like growth factor 1 may be another. Bilirubin Metabolism and Toxicity
In 1964 a group working with bilirubin metabolism and bilirubin toxicity was established in the Department of Pediatric Research by Jdrgen Fog (1918-1989). This work resulted in the following doctoral theses: Bilirubinutskillelsens Aktivering Hos Nyfddte [The Activation of Bilirubin Excretion in newborn^]'^ by Arne F. Bakken (1942-1990) in 1969, Albumin Binding and Toxicity of Bilirubin. The Protective Effect of Albumin on Bilirubin Toxicity and Factors Injluencing the Binding of Bilirubin to Albumin" by Dag Bratlid (1944-) in 1973,
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and Regulation of Hepatic UDP-Glucuronyltransfrase‘8 by Arnt Winsnes (1939-) in 1973. After a prolonged pause the bilirubin studies were restarted by Bratlid in 1983. The main results of these investigations are found in the thesis of Bratlid’s fellow Thor Willy Ruud Hansen (1946-), Bilirubin and Brain Toxicity. Studies on the E n t v , Localization, and Effects of Bilirubin in Rat Brain, published in 1988.” One important finding was that bilirubin inhibited synaptic activation, partly by inhibition of phosphorylation of synapsin 1,
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Thrombocytopenia in Children In 1981 Danish pediatric hematologist Jdrgen Cohn (1937-) joined the medical faculty at the University of TromsQ as professor of pediatrics. He had already defended his thesis Thrombocytopeni Hos Bdrn, en Ouersigt [Thrombocytopenia in Children, a Survey],20published in 1977. The thesis was based on a large epidemiologic study of thrombocytopenia in 433 children in Denmark.
Nordic Club for Pediatric Hematologists In the 1960s an increasing number of prominent pediatricians in the Nordic countries became interested in hematology, including Stig Sjolin and Lars Wranne in Sweden, Ruth Wegelius and Harri Nevanlinna in Finland, Torben Iversen in Denmark, and Martin Seip, Sverre Halvorsen, and Peter Johan Moe in Norway. During a meeting in Turku some of them met in Tuomas Peltonen’s sauna, and in this pleasant atmosphere decided to establish an informal Nordic Club for Pediatric Hematologists. The first meeting of this Club took place in Oslo on 1968. Thereafter meetings were arranged every year or every other year in one of the four Nordic countries on a rotation basis. Both benign hematology and leukemia were discussed. Gradually many of the club members became more and more involved in the treatment of leukemia, and somewhat later Wilms’ tumor and other solid tumors. Consequently in 1984 the Club merged with the pediatric oncologists to establish the formal Nordic Society for Pediatric Hematology and Oncology, NOPHO. Also in 1984 Jdrgen Cohn started the journal European Paediatric Haematology and Oncology, now known as Pediatric Hematology and Oncology.
European Society for Paediatric Haematology and Immunology During a meeting of the European Society for Paediatric Research (ESPR) in Interlaken in 1969, a special session for pediatric hematology was arranged. A decision was made to establish the European Society for Paediat-
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ric Haematology and Immunology (ESPHI). Active in this process were Walter Hitzig, Zurich; K.-H. Schafer, Hamburg; Stig Sjolin, Uppsala; and Martin Seip in Oslo; among others. The first president of the society was Stig Sjolin, and the first regular meeting was held in Stockholm in 1970. Seip has served as president of this society during two periods, 1970-1972 and 19771979.
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PEDIATRIC ONCOLOGY Modern pediatric oncology started in the late 1940s at the Children's Medical Center in Boston with the demonstration that remission could be achieved in some children with acute lymphocytic leukemia (ALL) by the use of folic acid antagonist, aminopterin.*' In Norway, systematic treatment of childhood leukemia with cytostatics was introduced by Martin Seip in Oslo in 1954, after his study period in Boston. In the beginning corticosteroids and aminopterin were the drugs used; soon 6-mercaptopurin, methotrexate, and vincristine were also used. At that time leukemia was thought to be incurable, but in the 1960s we gradually learned that with more intensive treatment cure was indeed possible. The first patients who were cured in the Oslo material developed leukemia in 1968. From the middle of the 1960s Peter Johan Moe, working at the time in Bergen, devoted much of his time to pediatric oncology, at first leukemia, then solid tumors. He later introduced modern pediatric oncology in Tromsd in 1972, and in Trondheim in 1978. In 1972, at Roswell Park Memorial Institute in Buffalo, a new approach to the chemotherapy of childhood ALL was introduced. Infusions of methotrexate 500 mg/m2 were given intravenously, followed by leucovorin rescue, as an important element in the consolidation phase of the treatment. Promising results were reported." As the first in Europe, Moe included this as part of the treatment protocol in Norway in 1975. This principle (later called intermediate dose methotrexate or IDM) was soon adopted by Seip in Oslo and Finne in Bergen. A National Norwegian Study using IDM was undertaken from 1975 to 1980, with remarkably good results for that time.23 Moe has with great enthusiasm advocated IDM and later high dose methotrexate (HDM), particularly in ALL. One advantage of IDM and HDM in the ALL protocol is that, in combination with intraspinal methotrexate injections, prophylactic irradiation of the central nervous system with its side effects can be avoided, a fact repeatedly stressed by Moe. Methotrexate metabolism and pharmacokinetics have been studied in detail in Trondheim by a visiting researcher from Hungary, Joseph Borsi. His main findings have been published in his 1988 thesis New Aspects ofthe Clinical
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Pharmacokinetics of Methotrexate. Studies in Children with Acute Lymphoblastic Leuke24 mia. In 1973, Moe started to register all new cases of leukemia and malignant lymphoma in Norwegian children. As of January 1, 1981, the Norwegian registry became part of a common Nordic registry in Uppsala, directed by Goran Gustafsson. Solid malignant tumors have been registered at the National Hospital in Oslo since 1980, from 1985 as part of a common Nordic registry in the Cancer Registry in Oslo, supervised by FrQydis Langmark. Moe and his coworkers in Trondheim have also performed a large study of the long-term results of leukemia patients in the Nordic countries. The results are presented in the thesis of Randi Nygaard (1945-) in 1991, Long-term Suruiual in Childhood Leukemia. Relapses and Late Effects After Completed Therapj,25 Two other pediatricians working at the University of Trondheim have written their theses on topics from hematology and oncology: BjQrn Magne Eggen (1950-) Studies in Cytotoxicity in Human Adherent Mononuclear Blood Cells in 1984,26and Rigmor Austgulen (1949-) Tumor Necrosis Factor: A Monocyte Derived Regulator of Cellular Growth in 1988.2’ In Oslo, Seip continued his involvement in ALL treatment until his retirement in 1988. From about 1970 Sverre 0. Lie (1938-) gradually took over the responsibility for treatment of acute myleoblastic leukemia (AML) and the solid tumors. The tumors have been treated in close collaboration with pediatric surgeons Ola Knutrud (1919-) and Thomas Monclair (1942-). Lie has enthusiastically devoted much of his time to pediatric oncology. One of his main fields of interest is the treatment of AML. In this field he is the coordinator of a Nordic treatment protocol which involves a tough cytostatic regimen combined with high doses of vitamin A. He is also engaged in an international neuroblastoma project. Lie has also established a unit for cell culture studies in the Department of Pediatric Research. Here, in collaboration with IngebjQrg Storm-Mathisen (1940-), Jon Helgestad (1950-) wrote his thesis In Vitro Hemopoiesis. A Study of Inhibitory Activities Under Different Culture Conditions, published in 1990.** An exciting research program has been conducted in recent years in a collaboration between Karl-Ludvig Reichelt (1933-) and coworkers in the Department of Pediatric Research, and Olav Hilmar Iversen (1923-), Kjell Elgjo (1933-), and coworkers in the Institute of Pathology of the National Hospital. Reichelt has isolated and characterized a “family” of small peptides that are tissue specific inhibitors of mitoses. Several of these have been synthesized. Their biologic activities have been studied in the Institute of Pathology. So far peptides from epidermis, colon, liver, and small intestine have been isolated and synthetized. The colonic peptide has been described by 0yvind Skraastad in 1989 in his thesis Isolation and Biological Properties of an Endogenous Inhibitor of Colonic Epithelial Cell Proliferation. 29
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In Bergen, Finn Wesenberg (1946-) has headed the pediatric oncology work since 1984. His thesis, published in 1981, was titled IgG, Other Proteins and Fcy Receptors Associated with Human Malignant Tissues. 30
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Nordic Society for Pediatric Hematology and Oncology (NOPHO)
In 1980 Swedish pediatric oncologists arranged a Nordic meeting in Orenas. The aim was to further Nordic cooperation in the field. In 1981 the Nordic Pediatric Leukemia Group was established, and a close collaboration on ALL treatment was begun. In 1984 NOPHO was formally established at a meeting in Reykjavik. The Nordic Club for Pediatric Hematologists was included in NOPHO. During the first four years Henrik Hertz from Denmark acted as Secretary General of NOPHO. Since 1988 Sverre 0. Lie has led the organization. Norwegian pediatric oncologists have actively participated in the Nordic collaboration in NOPHO, which has been stimulating and rewarding. The cooperative studies on leukemia treatment have been particularly important. A good medulloblastoma project has been carried out and several other projects are under way. SociCtC lnternationale d’Oncologie P4diatrique (SIOP)
SIOP, formally established in 1969, has gained an important role, and Norwegian pediatric oncologists have been stimulated by participating in SIOP activities. The first really dramatic progress in the treatment of solid tumors in children occurred in Wilms’ tumor, with a combination of surgery and cytostatic drugs. SIOP had several multicenter studies of Wilms’ tumor. From the Norwegian side, Moe and Lie have been the most active members of SIOP. Moe arranged a successful SIOP meeting in Trondheim in 1988. Lie has been member of the Board since 1987. He has convinced the Norwegian pharmaceutical company Nycomed to support the Society with an annual amount of $10,000 for 5 years. The amount is awarded by SIOP for particularly good papers and is known as the Nycomed prize. Support from Norwegian Cancer Societies
Without the generous support of cancer societies that have merged in the Norwegian Cancer Society, Norwegian pediatric oncology would be in poor shape. The Norwegian Cancer Society founded the first full-time position in pediatric oncology in Norway in 1984 (Ingebjdrg Storm-Mathisen), and sub-
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sequently founded similar positions in Bergen, Trondheim, and TromsB. It pays salaries for many other professionals (nurses, psychologists) in our units for pediatric oncology in Oslo, Bergen, Trondheim, and TromsB. The society also supports several research projects and has a subdivision for pediatric patients and their families. The Norwegian Cancer Society deserves our most sincere gratitude.
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REFERENCES 1. Salomonsen L. Morbus Hemorrhagicus neonatorum. Hypoprothrombinemia neonatorum [Bleeding disorder of hypoprothrombinemia in newborns]. Acta Paediatr. 1939;27(Suppl 41): 1-120. 2. Dam H . Cholesterinstoffwechsel in Hiihnereiern und in Hiinchen [Cholesterol metabolism in hen’s eggs and young hens]. Biochem Z. 1929;215:475-492. 3 . Dam H , Gerger A, Glavind J et al. Isolierung des Vitamins K in hochgereiniger Form [Isolation of vitamin K in highly purified form]. Helv Chim Acta. 1939;22:310-313. 4. Seip M . Reticulocyte studies. Acta Med Scand. 1953;146(Suppl 282):l-164. 5. Seip M, Halvorsen S. Erythrocyte production and iron stores in premature infants during the first months of life. The anemia of prematurity-etiology, pathogenesis, iron requirement. Acta Paediatr Scand. 1956;45:600-617. 6 . Imerslund 0. Idiopathic chronic megaloblastic anemia in children. Acta Paediatr Scand. 1960;49 (Suppl 1 19): 1-1 15. 7 . Imerslund 0, BjQrnstad P. Familial vitamin B,, malabsorption. Acta Haemat. 1963;30:1-7. 8. Seip M , Amlie R . Nye prinsipper i spebarnsernaeringen. Tidsskr Nor Laegeforen [New principles in infant nutrition]. 1957;77:729-734, 9. Moe PJ. Iron Requirements in Injancy, and Normal Blood Values during the First Ears of Life, Oslo, Norway: University of Oslo; 1965. Thesis. 10. Ek J. Folate Studies during Pregnancy, Lactation and Injany. Oslo, Norway: University of Oslo; 1986. Thesis. 11. Halvorsen S . The Central Neruous System in Regulation ojErythropoiesis. Oslo, Norway: University of Oslo; 1966. Thesis. 12. Finne P H . Studies of Erythropoietin. Oslo, Norway: University of Oslo; 1967. Thesis. 13. Lindemann R. Erythropoiesis Inhibitins Factor (EIF). Studies on the Urinary EIE Oslo, Norway: University of Oslo; 1976. Thesis. 14. HHgi P. The E a r 4 Anemia of Prematurity. Studies on the Role of Iron, Oxygen Exicity, and Erythropoietin. Oslo, Norway: University of Oslo; 1984. Thesis. 15. Sanengen T. Regulation of Erythropoiesis in the Neonatal Mammal during the Growth Period, Oslo, Norway: University of Oslo; 1989. Thesis. 16. Bakken AF. Bilirubinutskillelsens aktiuering hos nyfddte [The Activation of Bilirubin Excretion in Newborns]. Oslo, Norway: University of Oslo; 1969. Thesis. 17. Bratlid D. Albumin Binding and Toxicity of Bilirubin. The Protective Effect ofAlbumin on Bilirubin Toxicity and Factors InJuencing the Binding of Bilirubin to Albumin. Oslo, Norway: University of Oslo; 1973. Thesis. 18. Winsnes A. Regulation of Hepatic UDP-Glucuronyltran~erase.Oslo, Norway: University of Oslo; 1973. Thesis. 19. Hansen T W R . Bilirubin and Brain Exici(y. Studies on the Entry, Localization, and Effects of Bilirubin in R a t Brain. Oslo, Norway: University of Oslo; 1988. Thesis. 20. Cohn J . Trombocytopeni hos bdm, en ouersiyt [Thrombocytopenia in Children, a Survey]. Copenhagen, Denmark: University of Copenhagen; 1977. Thesis. 21. Farber S, Diamond LK, Mercer R D et al. Temporary remissions in acute leukemia in children produced by folk acid antagonist. N EnglJMed. 1948;238:787-793. 22. Wang JJ, Freeman AI, Sinks LF. Treatment of acute lymphocytic leukemia by high-dose intravenous methotrexate. Cancer Res. 1976:36: 1441-1444.
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23. Moe PJ, Seip M , Finne P H . Intermediate dose methotrexate (IDM) in childhood acute lymphocytic leukemia in Norway. Acute Paediatr Scand. 1981;70:73-79. 24. Borsi JD. N e w Aspects of the Clinical Pharmacokinetics of Methotrexate. Studies in Children with Acute Lymphoblastic Leukemia. Trondheim, Norway: University of Trondheim; 1988. Thesis. 25. Nygaard R. Long-Term Survival in Childhood Leukemia. Relapses and Late Effects After Completed Therapy. Trondheim, Norway: University of Trondheim; 1991. Thesis. 26. Eggen BM. Studies in Cytotoxicily in Human Adherent Mononwlear Blood Cells. Trondheim, Norway: University of Trondheim; 1984. Thesis. 27. Austgulen R. Tumor Necrosis Factor: A Monocyte-Derived Regulator of Cellular Growth. Trondheim, Norway: University of Trondheim; 1988. Thesis. 28. Helgestad J. In Vitro Hemopoiesis. A Study of Inhibitory Activities Under Di&nt Culture Conditions. Oslo, Norway: University of Oslo; 1990. Thesis. 29. Skraastad 0. Isolation and Biolojical Properties of an Endogenous Inhibitor of Colonic Epithelial Cell Prolifertion. Oslo, Norway: University of Oslo; 1989. Thesis. 30. Wesenberg F. IgG, Other Proteins and Fcy Receptors Associated with Human Mal%nant Tissues. Bergen, Norway: University of Bergen; 1981. Thesis. Received April 22, 1991 Accepted April 22, 1991 Address correspondence to M. Seip.
