STEM CELL KINETICS IN THE L 5222 RAT LEUKAEMIA

The behaviour of normal haemopoietic stem cells of the bone marrow during the development of the acute transferable rat leukaemia, L 5222, has been investigated. The granulopoietic committed stem cells, measured by the in vitro colony technique, showed a marked decrease to less than half normal levels. Pluripotent stem cells included in the small lymphocytes of the bone marrow, and labelled with ³H-thymidine by the complete labelling method, showed only a modest decrease in number and an unchanged labelling intensity. The results suggest that in this leukaemia the pluripotent stem cells may be affected in such a way that they are unable to react by proliferation to the depletion of the succeeding cell compartments. This might be due to inhibition by leukaemic cells or to a disturbed feedback regulation between the committed and pluripotent stem cell compartments.     

Treatment of Acute Lymphoblastic Leukaemia: PRELIMINARY REPORT BY THE LEUKAEMIA COMMITTEE AND THE WORKING PARTY ON LEUKAEMIA IN CHILDHOOD

One hundred and ninety-one cases of acute lymphoblastic leukaemia were entered in a trial in which, for five months, all received cytotoxic therapy with prednisolone, vincristine, mercaptopurine, L-asparaginase, and methotrexate (the latter in high dosage followed by folinic acid). Patients were then randomized to receive immunotherapy (B.C.G.), twice-weekly methotrexate, or no further treatment.One hundred and seventy-seven patients (93%) achieved full remission and at the time of analysis, 26 months from the beginning of the trial, 143 were still alive, including 70 in their first remission. Median “post-intensive” remission lengths were 17 weeks (no treatment), 27 weeks (B.C.G.), and 52 weeks (methotrexate). The prolongation of remission by methotrexate was most evident in those patients with low initial white cell counts. B.C.G. seemed to cause lymphocytosis but was without other conspicuous effect. The incidence of toxic reactions is reported, including an unusually low rate of anaphylaxis with L-asparaginase.These preliminary results are discussed and compared with those of similar trials.     

Distribution of Acute Leukaemia in Time and Space. Studies in New Zealand

The distribution of leukaemia in time and space was examined by tracing the date of onset and the place of residence in all cases of childhood leukaemia and of acute leukaemia in adults, totalling 1,003 cases, which occurred in New Zealand during the 12 years from 1953 to 1964.Significant seasonal variations in the onset were found in adults but not in children. Time-space clustering did not occur in adults, but a significant tendency towards it was found in children aged less than 6 years. Since a similar tendency has previously been found by two other groups of investigators it is suggested that leukaemia in young children may have a different aetiology from that occurring at other ages.     

GRANULOPOIESIS AND CELL KINETICS IN CHRONIC MYELOID LEUKAEMIA

The present study is an analysis of the kinetic data for chronic myeloid leukaemia derived from personal observations and cases reported in the literature. A comparison is made with the parameters for normal granulopoiesis and the growth pattern of the CML cell population discussed.     

FUNCTIONAL CELL COMPARTMENTS IN A RAT MODEL FOR HUMAN ACUTE MYELOCYTIC LEUKAEMIA

Functional cell compartments were studied in a rat model for human acute myelocytic leukaemia (AML). This was done by tracing the distribution of injected ⁵¹Chromium-labelled leukaemic cells in the body. It was concluded that two functional compartments can be distinguished in acute leukaemia, i.e., a rapidly exchangeable pool of cells (including the circulating blood pool, the marginal noncirculating blood pool and the rapidly exchangeable tissue pool; RETP) and a slowly exchangeable tissue pool (SETP). The sizes of these various compartments were roughly quantified at various stages of the disease by calculations based on the principle of isotope dilution and organ weight measurements. As the leukaemia progresses, the size of the SETP increases significantly relative to the size of the RETP. Simultaneously, the exchange rates of leukaemic cells between the organs and the blood decrease. The blood transit time of leukaemic cells was also significantly prolonged, as is the case in human AML.     

Temporal trends in childhood leukaemia incidence following exposure to radioactive fallout from atmospheric nuclear weapons testing

Notably raised rates of childhood leukaemia incidence have been found near some nuclear installations, in particular Sellafield and Dounreay in the United Kingdom, but risk assessments have concluded that the radiation doses estimated to have been received by children or in utero as a result of operations at these installations are much too small to account for the reported increases in incidence. This has led to speculation that the risk of childhood leukaemia arising from internal exposure to radiation following the intake of radioactive material released from nuclear facilities has been substantially underestimated. The radionuclides discharged from many nuclear installations are similar to those released into the global environment by atmospheric nuclear weapons testing, which was at its height in the late-1950s and early-1960s. Measurements of anthropogenic radionuclides in members of the general public resident in the vicinity of Sellafield and Dounreay have found levels that do not differ greatly from those in persons living remote from nuclear installations that are due to ubiquitous exposure to the radioactive debris of nuclear weapons testing. Therefore, if the leukaemia risk to children resulting from deposition within the body of radioactive material discharged from nuclear facilities has been grossly underestimated, then a pronounced excess of childhood leukaemia would have been expected as a consequence of the short period of intense atmospheric weapons testing. We have examined childhood leukaemia incidence in 11 large-scale cancer registries in three continents for which data were available at least as early as 1962. We found no evidence of a wave of excess cases corresponding to the peak of radioactive fallout from atmospheric weapons testing. The absence of a discernible increase in the incidence of childhood leukaemia following the period of maximum exposure to the radioactive debris of this testing weighs heavily against the suggestion that conventional methods are seriously in error when assessing the risk of childhood leukaemia from exposure to man-made radionuclides released from nuclear installations.     

EXCLUSION OF SERUM FACTORS IN THE IN-VITRO DEPRESSION OF LYMPHOCYTES' RESPONSE TO MITOGENS IN CHRONIC LYMPHOCYTIC LEUKAEMIA

To find out whether serum factors are involved in the depression of the mitogenic response of lymphocytes of patients with chronic lymphocytic leukaemia, sera from these patients were used in the culture medium for normal lymphocytes. the results were considered on the basis of the dynamics of responses of these normal lymphocytes, comparing a standard human group AB serum with twenty sera from patients with CLL. No heat-stable inhibitory factors peculiar to CLL were found. In an experiment in which fresh CLL and normal sera were compared, no heat-labile inhibitory factors were apparent.     

Incidence of leukaemia and other cancers in birth and schools cohorts in the Dounreay area.

OBJECTIVE--To determine whether a raised incidence of leukaemia in the Dounreay area occurred in children born to local mothers (birth cohort) or in those who moved to the area after birth (schools cohort) and also whether any cases of cancer have occurred in children born near Dounreay who may have moved elsewhere. DESIGN--Follow up study. SETTING--Dounreay area of Caithness, Scotland. SUBJECTS--4144 children born in the area in the period 1969-88 and 1641 children who attended local schools in the same period but who had been born elsewhere. MAIN OUTCOME MEASURES--Cancer registration records linked to birth and school records with computerised probability matching methods. RESULTS--Five cancer registrations were traced from the birth cohort compared with 5.8 expected on the basis of national rates (observed to expected ratio 0.9, 95% confidence interval 0.3 to 2.0). All five cases were of leukaemia (2.3, 0.7 to 5.4). In the schools cohort three cases were found (2.1, 0.4 to 6.2), all of which were of leukaemia (6.7, 1.4 to 19.5). All eight children were resident in the Dounreay area at the time of diagnosis; thus no cases were found in children who were born in or had attended school in the study area but who subsequently moved away. CONCLUSION--The raised incidence of leukaemia in both the birth and schools cohorts suggests that place of birth is not a more important factor than place of residence in the series of cases of leukaemia observed near Dounreay area.     

The risk of leukaemia in young children from exposure to tritium and carbon-14 in the discharges of German nuclear power stations and in the fallout from atmospheric nuclear weapons testing

Towards the end of 2007, the results were published from a case–control study (the “KiKK Study”) of cancer in young children, diagnosed <5 years of age during 1980–2003 while resident near nuclear power stations in western Germany. The study found a tendency for cases of leukaemia to live closer to the nearest nuclear power station than their matched controls, producing an odds ratio that was raised to a statistically significant extent for residence within 5 km of a nuclear power station. The findings of the study received much publicity, but a detailed radiological risk assessment demonstrated that the radiation doses received by young children from discharges of radioactive material from the nuclear reactors were much lower than those received from natural background radiation and far too small to be responsible for the statistical association reported in the KiKK Study. This has led to speculation that conventional radiological risk assessments have grossly underestimated the risk of leukaemia in young children posed by exposure to man-made radionuclides, and particular attention has been drawn to the possible role of tritium and carbon-14 discharges in this supposedly severe underestimation of risk. Both ³H and ¹⁴C are generated naturally in the upper atmosphere, and substantial increases in these radionuclides in the environment occurred as a result of their production by atmospheric testing of nuclear weapons during the late 1950s and early 1960s. If the leukaemogenic effect of these radionuclides has been seriously underestimated to the degree necessary to explain the KiKK Study findings, then a pronounced increase in the worldwide incidence of leukaemia among young children should have followed the notably elevated exposure to ³H and ¹⁴C from nuclear weapons testing fallout. To investigate this hypothesis, the time series of incidence rates of leukaemia among young children <5 years of age at diagnosis has been examined from ten cancer registries from three continents and both hemispheres, which include registration data from the early 1960s or before. No evidence of a markedly increased risk of leukaemia in young children following the peak of above-ground nuclear weapons testing, or that incidence rates are related to level of exposure to fallout, is apparent from these registration rates, providing strong grounds for discounting the idea that the risk of leukaemia in young children from ³H or ¹⁴C (or any other radionuclide present in both nuclear weapons testing fallout and discharges from nuclear installations) has been grossly underestimated and that such exposure can account for the findings of the KiKK Study.     

Trends in childhood leukaemia in the Nordic countries in relation to fallout from atmospheric nuclear weapons testing.

OBJECTIVE--To obtain further information about the risks of childhood leukaemia after exposure to ionising radiation at low doses and low dose rates before or after birth or to the father''s testes shortly before conception. DESIGN--Observational study of trends in incidence of childhood leukaemia in relation to estimated radiation exposures due to fallout from atmospheric nuclear weapons testing during the 1950s and 1960s. SETTING--Nordic countries. SUBJECTS--Children aged under 15 years. MAIN OUTCOME MEASURES--Incidence rates of leukaemia by age at diagnosis, sex, country, and calendar year of diagnosis or year of birth; exposure category; relation between leukaemia and exposure for children aged 0-14 and 0-4 separately. RESULTS--During the high fallout period the average estimated dose equivalent to the fetal red bone marrow was around 140 mu Sv and the average annual testicular dose 140 mu Sv. There was little evidence of increased incidence of leukaemia among children born in these years. Doses to the red bone marrow of a child after birth were higher, and during the high exposure period children would have been subjected to an additional dose equivalent of around 1500 mu Sv, similar to doses received by children in several parts of central and eastern Europe owing to the Chernobyl accident and about 50% greater than the annual dose equivalent to the red bone marrow of a child from natural radiation. leukaemia incidence and red marrow dose was not related overall, but rates of leukaemia in the high exposure period were slightly higher than in the surrounding medium exposure period (relative risk for ages 0-14: 1.07, 95% confidence interval 1.00 to 1.14; for ages 0-4: 1.11, 1.00 to 1.24). CONCLUSIONS--Current predicted risks of childhood leukaemia after exposure to radiation are not greatly underestimated for low dose rate exposures.     

Risk of acute childhood leukaemia in Sweden after the Chernobyl reactor accident. Swedish Child Leukaemia Group.

OBJECTIVE--To evaluate the risk of acute childhood leukaemia in areas of Sweden contaminated after the Chernobyl reactor accident in April 1986. DESIGN--Population based study of childhood leukaemia diagnosed during 1980-92. SETTING--Coordinates for places of residence of all 1.6 million children aged 0-15 years; aerial mapped areas of Sweden heavily contaminated after the Chernobyl accident. SUBJECTS--888 children aged 0-15 years with acute leukaemia diagnosed in Sweden during 1980-92, identified with place of birth and residence at diagnosis. MAIN OUTCOME MEASURES--Risk of leukaemia in areas contaminated after the Chernobyl accident compared with the rest of Sweden and in the same areas before the accident. RESULTS--During six and a half years of follow up after the accident the odds ratio for acute leukaemia was 0.9 (95% confidence interval 0.6 to 1.4) in highly contaminated areas (> or = 10 kBq/m2) compared with the same areas before the accident. For the subgroup acute lymphoblastic leukaemia in children aged under 5 years at diagnosis the odds ratio was 1.5 (0.8 to 2.6). For all cases diagnosed after May 1986 in highly contaminated areas compared with areas of low contamination the odds ratio was 0.9 (0.7 to 1.3). For acute lymphoblastic leukaemia in children aged under 5 years at diagnosis the odds ratio was 1.2 (0.8 to 1.9) in highly contaminated areas compared with areas of low contamination. Dose-response analysis showed no correlation between the degree of contamination and the incidence of childhood leukaemia. CONCLUSION--There has been no significant increase in the incidence of acute childhood leukaemia in areas of Sweden contaminated after the Chernobyl reactor accident.     

Childhood leukaemia in the West Berkshire and Basingstoke and North Hampshire District Health Authorities in relation to nuclear establishments in the vicinity.

During the years 1972-85, 89 children aged 0-14 were registered with leukaemia in the West Berkshire and Basingstoke and North Hampshire District Health Authorities. Two nuclear establishments are located within the health authorities, and a third is situated nearby. Fifty of the 143 electoral wards in the two district health authorities lie wholly within, or have at least half their area lying within, a circle of radius 10 km around the establishments. In those 50 electoral wards 41 children aged 0-14 were registered with leukaemia, 28.6 registrations being expected on the basis of leukaemia registration rates in England and Wales (incidence ratio = 1.4, p less than 0.05). This excess was confined to children aged 0-4, among whom there were 29 registrations of leukaemia, 14.4 being expected (incidence ratio = 2.0, p less than 0.001). In the remaining 93 electoral wards there was a small and non-significant increase in the number of registrations of leukaemia at age 0-14 (48 observed, 40.8 expected; incidence ratio = 1.2). There was no obvious trend in the incidence of childhood leukaemia over the 14 years and the overall occurrence of the malignancy in the 143 electoral wards was consistent with a random distribution. In the surrounding Oxford and Wessex Regional Health Authorities the number of registrations of leukaemia at age 0-14 was virtually identical with that expected on the basis of registration rates in England and Wales (362 observed, 372.5 expected; incidence ratio = 1.0). These data indicate that in the two district health authorities studied there was an excess incidence of childhood leukaemia during 1972-85 in the vicinity of the nuclear establishments. In the West Berkshire and Basingstoke and North Hampshire District Health Authorities an average of 60,000 children aged 0-14 lived within a 10 km radius of a nuclear establishment each year. The normal expectation of leukaemia in these children was two cases a year, whereas the recorded incidence was three cases per year, representing one extra case of leukaemia each year among these 60,000 children.     

Wartime evacuation and mortality from childhood leukaemia in England and Wales in 1945-9.

OBJECTIVE--To discover whether the wartime government evacuation of children from London and other population centres to rural districts was associated with any increase in childhood leukaemia. DESIGN--Observational study of mortality from leukaemia among the childhood population of England and Wales in relation to the unique population movements during the second world war. The 476 rural districts of England and Wales were ranked according to the ratio of government evacuees (two thirds of them children) to local children in September 1941. The districts were divided into three categories, each with similar numbers of children in 1947 but with different ratios of evacuees to local children ("low," "intermediate," "high"). Mortality from childhood leukaemia was examined in these three rural categories in 1945-9. Urban areas were also examined according to their exposure to evacuees. SETTING--Local authority areas of England and Wales. SUBJECTS--Children aged under 15. RESULTS--47% excess of leukaemia at ages 0-14 years occurred in 1945-9 in the rural "high" category for evacuees relative to the "low" category, with a significant trend across the three categories. There were increases in both the 0-4 and 5-14 year age groups, but these were larger in the older age group. Rates 25% lower than average occurred in rural areas with few evacuees. CONCLUSION--These findings suggest that wartime evacuation increased the incidence of childhood leukaemia in rural areas and that other forms of population mixing may have contributed to the increases in past decades. Overall, they add to the appreciable evidence for an infective basis in childhood leukaemia.     

Mortality and morbidity caused by measles in children with malignant disease attending four major treatment centres: a retrospective review.

Measles is a major cause of mortality and morbidity in children receiving treatment for leukaemia. A review was made of all the documented cases of measles in children in first remission from acute lymphoblastic leukaemia at four major treatment centres in 1974-84. Over the 11 years reviewed 1043 children with acute lymphoblastic leukaemia were referred to these centres. Fifty one (4.9%) died while in first remission and 15 (29.4%) of these deaths were due to measles or its complications: 12 cases of pneumonia, 10 of them fatal; and six cases of encephalitis, five of them fatal and the sixth child left severely handicapped. These children would have had at least a 50% chance of long term survival. The severity of measles in the immunocompromised patient reinforces the need to improve the poor uptake of measles immunisation in Britain.     

Neonatal vitamin K administration and childhood cancer in the north of England: retrospective case-control study.

OBJECTIVE: To explore the possible association between intramuscular vitamin K given to neonates and the subsequent development of childhood cancer. DESIGN: Retrospective case-control study on the basis of hospital records. SETTING: The former Northern Health region of England. SUBJECTS: 685 children who were born and lived in the region and who developed cancer before their 15th birthday, and 3442 controls also born between 1960 and 1991 and matched only for date and hospital of birth. The notes of a further 701 index cases were untraceable. MAIN EXPOSURE MEASURE: Administration of intramuscular vitamin K versus no exposure to vitamin K. RESULTS: There was no association between the administration of vitamin K and the development of all childhood cancers (unadjusted odds ratio 0.89; 95% confidence interval 0.69 to 1.15) or for all acute lymphoblastic leukaemia (1.20; 0.75 to 1.92), but there was a raised odds ratio for acute lymphoblastic leukaemia developing 1-6 years after birth (1.79; 1.02 to 3.15). No such association was seen in a separate cohort-based study not dependent on case note retrieval in which the rates of acute lymphoblastic leukaemia in children born in hospital units where all babies received vitamin K were compared with those born in units where less than a third received prophylaxis. CONCLUSIONS: It is not possible, on the basis of currently published evidence, to refute the suggestion that neonatal intramuscular vitamin K administration increases the risk of early childhood leukaemia. Any association may have been masked in earlier studies that did not use controls matched for time and locality by other unidentified factors affecting the spatiotemporal variations in incidence of leukaemia.     

DNA SYNTHESIS TIME IN LEUKAEMIC CELLS AS MEASURED BY THE DOUBLE LABELLING AND THE PERCENTAGE LABELLED MITOSES METHODS

Values of T _s provided by the double labelling method have been compared with those given by the percentage labelled mitoses curve for blast cells in the peripheral blood of a patient with plasma cell leukaemia and of rats bearing a transferable acute leukaemia. the double labelling method was carried out giving the first label (³H-thymidine) in vivo and the second label (¹⁴C-thymidine) in vitro with several values for the interval between the two labels. T _s was calculated by fitting regression lines to the results obtained. Data for percentage labelled mitoses were analysed by computer. For the plasma cell leukaemia values of T _s= 17.1 ± 7.0 hr and T _s= 19.8 ± 3.4 hr, and for the rat leukaemia values of 8.7 ± 1.7 hr and 9.0 ± 1.7 hr (7.1 hr corrected for exponential growth) were obtained from the percentage labelled mitoses and double labelling methods respectively. It is concluded that the double labelling method is valid for the study of cell proliferation in leukaemic blast cells.     

Bone marrow transplantation in childhood leukaemia--experience and strategies in the Federal Republic of Germany

BMT has gained its place in the treatment of childhood leukaemia. Nevertheless, there are still many questions open. In acute lymphoblastic leukaemia children should normally be grafted in 2nd remission (CR). Some high risk cases, however, should probably be grafted in 1st CR. It is not clear whether children with late relapses benefit more from BMT than from renewed chemotherapy. Children with a relapse during maintenance therapy, however, have a better survival rate with BMT. In acute nonlymphoblastic leukaemia certain high risk patients should be grafted in 1st CR but it has still to be shown that BMT is superior to chemotherapy in such cases. It is not clear whether children with a relapse following intensive chemotherapy (such as the BFM-protocols) will benefit from BMT at all. In chronic myelocytic leukaemia, BMT in chronic phase should be performed. Thus, for the first time cure has become possible for this disease. Waiting for acceleration or even the occurrence of a blast crisis decreases the chance of survival after BMT dramatically. Since complications of BMT such as graft-versus-host reaction or severe infections are less frequent in children, relapses remain the main problem after BMT in childhood leukaemia.     

ELF magnetic fields: animal studies, mechanisms of action

Animal studies can contribute to addressing the issue of possible greater health risk for children exposed to 50–60 Hz extremely low frequency (ELF) magnetic fields (MFs), mostly in terms of teratological effects and cancer.Teratology has been extensively studied in animals exposed to ELF MFs but experiments have not established adverse developmental effects.Childhood leukaemia has been the only cancer consistently reported in epidemiological studies as associated with exposure to ELF MFs. This association has been the basis for the classification as “possibly carcinogenic to humans” by the International Agency for Research on Cancer in 2002. Animal experiments have provided only limited support for these epidemiological findings. However, none but one study used an animal model for acute lymphoblastic leukaemia (ALL), the main form of childhood leukaemia, and exposures to ELF MFs were not carried out over the whole pregnancy period, when the first hit of ALL is assumed to occur.Moreover, there are no generally accepted biophysical mechanisms that could explain carcinogenic effects of low-level MFs. The radical pair mechanism and related cryptochromes (CRY) molecules have recently been identified in birds and other non-mammalian species, as a sensor of the geomagnetic field, involved in navigation. The hypothesis has to be tested in mammalian models. CRY, which is part of the molecular circadian clock machinery, is a ubiquitous protein likely to be involved in cancer cell growth and DNA repair.In summary, we now have some clues to test for a better characterization of the interaction between ALL and ELF MFs exposure.     

Childhood cancer in relation to distance from high voltage power lines in England and Wales: a case-control study

Objective To determine whether there is an association between distance of home address at birth from high voltage power lines and the incidence of leukaemia and other cancers in children in England and Wales.Design Case-control study.Setting Cancer registry and National Grid records.Subjects Records of 29 081 children with cancer, including 9700 with leukaemia. Children were aged 0-14 years and born in England and Wales, 1962-95. Controls were individually matched for sex, approximate date of birth, and birth registration district. No active participation was required.Main outcome measures Distance from home address at birth to the nearest high voltage overhead power line in existence at the time.Results Compared with those who lived > 600 m from a line at birth, children who lived within 200 m had a relative risk of leukaemia of 1.69 (95% confidence interval 1.13 to 2.53); those born between 200 and 600 m had a relative risk of 1.23 (1.02 to 1.49). There was a significant (P < 0.01) trend in risk in relation to the reciprocal of distance from the line. No excess risk in relation to proximity to lines was found for other childhood cancers.Conclusions There is an association between childhood leukaemia and proximity of home address at birth to high voltage power lines, and the apparent risk extends to a greater distance than would have been expected from previous studies. About 4% of children in England and Wales live within 600 m of high voltage lines at birth. If the association is causal, about 1% of childhood leukaemia in England and Wales would be attributable to these lines, though this estimate has considerable statistical uncertainty. There is no accepted biological mechanism to explain the epidemiological results; indeed, the relation may be due to chance or confounding.