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Human peripheral blood mononuclear cell cultures (PBMC) stimulated with Sendai virus or K562 cells produce a mixture of interferons. Temperature and pH stability characteristics and reactions with monospecific antibodies indicate that PBMC cultures from adults produce interferons alpha and gamma in approximately equal proportions. PBMC cultures from children produce lower levels of interferons with a higher proportion of type alpha. The ability of PBMC cultures from children with acute lymphoblastic leukaemia (ALL) to produce interferon was determined. Little or no gamma interferon was induced by either Sendai virus or K562 cells. Cultures from some children with ALL produced alpha interferon but mean levels were significantly lower than from normal children. A group of older children with ALL who had completed their course of therapy and were off treatment produced levels of interferon indistinguishable from those of normal children. This in vitro deficit, possibly induced by chemotherapy, may reflect an in vivo deficit and may contribute to the impaired handling of viruses seen in children being treated for ALL.

The absorption of oral methotrexate (MTX) has been studied in 124 children with acute lymphoblastic leukemia (ALL). Blood levels of MTX were very variable and unpredictable. There was a 20-fold difference between the highest and lowest peak level achieved. Division into two groups has shown that those children who absorb MTX slowly have a worse disease-free survival. It is possible that MTX damages the intestinal mucosa and causes a malabsorption of itself in some children. It is suggested that future protocols for the treatment of ALL should include pharmacokinetic studies, which may help to explain the unexpected relapses of good prognosis patients and lead to the development of more effective treatment.

A previous study has shown that significant intellectual deficits exist in children treated for leukaemia but not in those with solid tumours. Unexpectedly, the deficits had not increased in the two years since the original study, suggesting that the nadir had already been reached five years after diagnosis.

Serum methotrexate concentrations have been measured in 28 children with acute lymphoblastic leukaemia (ALL) following PO administration under standard conditions. Small-intestinal transit time, measured by the time taken for lactulose to pass from mouth to caecum, has been related with methotrexate absorption parameters. Small intestinal transit times ranged from 30 to 240 min. Children with longer transit times had later times of peak methotrexate concentration and tended to have a more erratic methotrexate absorption profile with two peaks. There appears to be an optimal transit time between 90 and 105 min for methotrexate absorption, with both faster and slower small-intestinal transit times producing lower peak concentrations as a fraction of the dose.

Repeated methotrexate absorption studies were performed under standard conditions in 127 children receiving either oral or intramuscular methotrexate for acute lymphoblastic leukaemia. There was marked variability in peak concentration, area under the serum concentration curve and clearance both between patients and in repeated studies on the same patient. Although the intramuscular route produced higher serum concentrations and AUC than the oral route, variability within and between patients was considerable and was most marked at higher concentrations. Neither age or sex could account for variation in methotrexate absorption or clearance. Intramuscular methotrexate, although producing higher serum concentrations and AUC, does not reduce the variability observed with oral administration. Prediction of subsequent methotrexate concentrations from the knowledge of one absorption profile is not possible.

Twenty-four consecutive deaths from a total of 70 children receiving treatment for acute lymphoblastic leukaemia (ALL) have been reviewed. An attempt has been made to ascribe the cause of death to either infection, haemorrhage, the leukaemia itself, or a combination of these factors. No child was free of infection at death. Infection, with or without haemorrhage, was responsible for the deaths of all 15 children whose leukaemia had not relapsed. Although infection was present at death in all 9 children whose leukaemia had relapsed, the leukaemia process itself was also a major contributing factor. Viruses were associated with death in many of the children and may be emerging as important pathogens in children with ALL. Familiarity with a protocol may be an important factor in the prevention of fatal infections in such children. Centralization of treatment is necessary if this expertise is to be acquired.

Small bowel function before, during, and after treatment for acute lymphoblastic leukaemia was studied in 26 children. A significant impairment of D-xylose absorption was found during treatment. Permeability studies showed a significant decrease in mannitol and a significant increase in lactulose concentrations; five of 20 children tested had evidence of lactose malabsorption, three of whom were symptomatic. Intestinal function abnormalities were greater in children whose methotrexate treatments were separated by 7 day than by 16 day intervals. Only five (19%) children had no abnormal tests. Abnormalities of small bowel function may be treatment induced and this has implications for morbidity from gastrointestinal symptoms, impairment of the mucosal barrier, and malabsorption of both nutrients and drugs leading to malnutrition and suboptimal drug concentrations.

Thirty children with acute lymphoblastic leukaemia (ALL) were studied and had a virus isolated. Only 50% produced a significant rise in complement fixing (CF) antibody titre compared to 100% of normal children. The failure to produce antibodies was unpredictable. CF antibodies are not a reliable guide to virus infections in children with ALL.

A one-hour D-xylose absorption test was performed on 18 children with acute lymphoblastic leukaemia. Xylose absorption was normal in children who had not received methotrexate, but there was a significant degree of malabsorption in those who had taken methotrexate within the previous seven days. There was a progressive and significant increase in malabsorption related to the cumulative dose of methotrexate. These findings provide further evidence that regular methotrexate treatment every seven days is more toxic than if it is more widely spaced. The spacing of treatment is currently under investigation.

A new spatial analysis device called a Geographical Analysis Machine detects deviations from the Poisson distribution of rare events. Application to childhood leukaemia data from the north of England identified five clusters, only one of which had been noted by previous methods.

Eight of 36 children receiving maintenance chemotherapy for acute lymphoblastic leukaemia or non-Hodgkin's lymphoma had liver biopsies on the basis of clinical abnormalities and/or elevated serum enzyme levels. Six biopsies were abnormal, including one in a boy with spider naevi who showed micronudular cirrhosis; he appeared to retain methotrexate in the blood for a prolonged period and his SGOT level did not return to normal for 19 months after maintenance chemotherapy was discontinued. The five other abnormal biopsies showed minor changes in the portal tracts. The six children with abnormal liver histology showed a wide variation in their early handling of an oral methotrexate dose. There was a statistically significant rise in mean SGOT and alkaline phosphatase during treatment, but the wide scatter in values precluded their use as accurate indicators of liver damage in these children.

Nasal concentrations of leucocyte interferon measured immunoradiometrically were appreciably higher in children infected with influenza viruses than those infected with paramyxoviruses. Regardless of the infecting virus, leukaemic children produced normal amounts of interferon, but this appeared to have little effect on the duration of excretion of virus.

Fifteen children with acute lymphoblastic leukaemia (ALL) in remission receiving maintenance chemotherapy and 12 ALL patients off treatment and in remission were tested for natural killer (NK) cell activity in vitro. Compared with a control population the children with ALL receiving maintenance chemotherapy had low levels of NK cell activity. This effect was not due to a specific reduction in NK cell numbers since proportions of mononuclear cells detected by the monoclonal antibodies HNK-1 (Leu-7) and Leu-11a were normal. Furthermore NK cell activity in patients could only be partially increased by pre-incubation of effector cells with interferon (alpha IFN). These studies confirm the lack of NK cell activity in children with ALL and show that this phenomenon is directly related to functional NK cell impairment. Our study has further shown that this effect is transient since ALL patients off treatment and in remission showed normal levels and augmentation of NK cell activity.

The pattern of virus isolation and illness was studied in 64 children with acute lymphoblastic leukaemia (ALL) during periods of apparent infection and when the children were well. The virus isolation rate of 2.2 viruses per child a year is similar to that previously found in normal children. In only 32% of children with symptoms were viruses found and 14.5% had viruses isolated when asymptomatic. The children with ALL appear to be more vulnerable to multiple virus infections and to excrete the virus for longer periods. This may be due to failure of production of both local and systemic antibodies. The failure in the past to recognise the true importance of virus infections in ALL may have been due to inadequate diagnostic techniques.

As part of a wider survey of infections and defence mechanisms, concentrations of serum immunoglobulins IgG, IgA, and IgM were measured regularly by single radial immunodiffusion in a group of children receiving treatment for acute lymphoblastic leukaemia while in their first remission. IgM concentrations were often markedly raised at diagnosis, and IgG and IgA concentrations both began falling within one month of diagnosis. Four months after diagnosis all three had fallen significantly, but this tendency stopped after six months. Only IgG partially recovered, and non returned to pretreatment concentrations even in children followed for two years. The results suggest that vincristine and prednisone are the major factors that initiated the fall in IgG and IgA. Lowered IgM concentrations may have been due to cranial irradiation or continuous maintenance treatment, or both.

Serial studies of numbers of circulating T and B lymphocytes at monthly intervals in children with acute lymphoblastic leukaemia showed a marked fall in the number of B cells, relatively greater than that of T cells, early in the course of maintenance chemotherapy and immediately after a course of cranial irradiation. The fall in the number of B cell is not a consequence of long-term chemotherapy, and is possibly related to a specific event such as cranial irradiation.

Neutrophil function was assessed regularly in 26 children with acute lymphoblastic leukaemia (ALL) in remission, both when they were well and during viral infections. Tests of candidacidal ability when these children were apparently free of infection showed a trend towards lower levels compared with controls. The most pronounced depression of candidacidal ability and chemotaxis was during viral infections, and these two functions of neutrophils were more likely to be abnormal then than when the children were free of infection. In children with ALL in remission, whose neutrophils may function abnormally even when they are well, the risk of acquiring bacterial or fungal infections may be made greater by virus infections.