Acute neurotoxicity in children with advanced stage B-non-Hodgkin's lymphoma and B-acute lymphoblastic leukaemia treated with the United Kingdom children cancer study group 9002/9003 protocols.

We reviewed the pattern of acute neurotoxicity in children with B-non-Hodgkin's lymphoma (B-NHL) and B-acute lymphoblastic leukaemia (ALL) treated with the UKCCSG 9002/9003 protocols. Among 175 patients, 21 (12%) developed acute neurotoxicity: 9002 protocol (n=11/112) and 9003 (n=10/63). There were 20 boys and the median age was 10 years. Patients with neurological symptoms due to other causes were excluded. Acute neurological symptoms developed following induction chemotherapy in 7 patients, or after a more intensive course of chemotherapy containing high-dose methotrexate (n=14). Nine patients required their chemotherapy to be altered because of the acute neurotoxicity. One patient died of cerebral haemorrhage but none of the remaining six deaths was attributed to acute neurotoxicity. We conclude that acute neurotoxicity is common in children treated with the 9002/9003 protocols and tends to be transient. Intrathecal and systemic chemotherapy including high-dose methotrexate is probably the most common predisposing factor. Modification of subsequent chemotherapy is not invariably necessary.

Outcome of relapsed or refractory childhood B-cell acute lymphoblastic leukaemia and B-cell non-Hodgkin's lymphoma treated with the UKCCSG 9003/9002 protocols.

Twenty-six children with B-cell acute lymphoblastic leukaemia (B-ALL) or Murphy Stage III or IV B-cell non-Hodgkin's lymphoma (B-NHL) progressed or relapsed after first-line therapy with a short, intensive multiagent chemotherapy regimen [United Kingdom Childhood Cancer Study Group (UKCCSG) 9003] (n = 62) or a slightly less intensive regimen (UKCCSG 9002) (n = 112). Eight patients (4.6%) never achieved complete remission (CR) and 18 (10.3%) relapsed. Second-line therapy resulted in remission for eight patients (30%). All patients initially treated with the 9003 protocol died. Three patients (11.5%) in the 9002 group, including one who never achieved CR in the primary site, are alive after second-line therapy. This study confirms that the prognosis of relapsed or refractory B-ALL/B-NHL is poor and exceptionally so if relapse occurred less than 6 months from diagnosis. High-dose therapy with stem cell rescue was used in only seven patients; its role needs to be studied further.

Improved outcome in children with advanced stage B-cell non-Hodgkin's lymphoma (B-NHL): results of the United Kingdom Children Cancer Study Group (UKCCSG) 9002 protocol.

From July 1990 to March 1996, 112 children with stage III or IV B-cell non-Hodgkin's lymphoma (B-NHL) with up to 70% FAB L3-type blasts (n = 42) in the bone marrow without central nervous system (CNS) disease were treated on the United Kingdom Children Cancer Study Group (UKCCSG) 9002 protocol (identical to the French LMB 84). The median age was 8.3 years. There were 81 boys and 31 girls. According to the extent of the primary disease, patients were sub-staged into three groups: IIIA with unresectable abdominal tumour (n = 39); IIIB with abdominal multiorgan involvement (n = 57) and IIIX with extra-abdominal primary lymphoma often presenting as pleural effusion (n = 16). Univariate and multivariate analyses were carried out to evaluate the prognostic significance of lactate dehydrogenase (LDH) level at diagnosis, the sub-stage and the time to achieve complete remission (CR). With a median follow up of 48 months (range 12-92), the overall and event free survival (EFS) is 87% (95% confidence interval (CI) 79.2-92.1 %) and 83.7% (95% CI 76.3-89.2%) respectively. Six patients (5.4%) never achieved CR, of whom one is alive following high-dose therapy. Eight patients (7.1%) relapsed after achieving CR, three are alive after second-line therapy. There were three early toxic deaths (2.7%), mainly from infection, and one late death from a second cancer. There was no significant difference in EFS according to LDH level at diagnosis, the sub-stage or the time to CR. This study confirms the overall good prognosis and low rate of toxic deaths in patients with advanced B-NHL treated with this intensive regimen. No significant difference in EFS according to the sub-stage, the time to achieve CR or LDH level at diagnosis making it difficult to identify a group that should not receive intensive therapy.

Improved cure rate in children with B-cell acute lymphoblastic leukaemia (B-ALL) and stage IV B-cell non-Hodgkin's lymphoma (B-NHL)--results of the UKCCSG 9003 protocol.

From June 1990 to February 1996, 35 patients with B-cell acute lymphoblastic leukaemia (B-ALL) 13 of whom had CNS disease and 28 patients with stage IV B-cell non-Hodgkin's lymphoma (B-NHL) 22 of whom had CNS involvement were treated with a short, intensive multiagent chemotherapy regimen (UKCCSG 9003 protocol) based on the French LMB 86 regimen. Fifty-five were boys. The age range was 11 months to 16.5 years (median 8.4 years). Chemotherapy included cyclophosphamide, vincristine, daunorubicin, high-dose methotrexate (COPADM) and etoposide/high-dose cytarabine (CYVE) with frequent intrathecal (i.t.) triple therapy (methotrexate, cytarabine and hydrocortisone). Cranial irradiation (24 Gy in 15 fractions) was recommended in patients with overt CNS disease. One patient with Wiskott-Aldrich syndrome was withdrawn after entry and has been excluded from the analysis. Ten patients (16%) have relapsed (CNS, four; BM, two; combined CNS and BM, three; and jaw, one) 4-11 months after diagnosis and two patients never achieved complete remission (CR). All have died. In seven of the patients who relapsed, treatment had been modified or delayed because of poor clinical condition. Seven patients (11%) died of toxicity 11 days to 4 months after diagnosis. The cause of death was sepsis (n = 5) or sepsis with renal failure (n = 2). With a median follow-up of 3.1 years from diagnosis (range 9 months to 6.3 years), 43 patients (69%) survive in CR. This study confirms the effectiveness of this regimen with regard to the relapse rate (16%), although the rate of toxic death is of concern.

The effect of complete excision on stage III neuroblastoma: a report of the European Neuroblastoma Study Group.

UNLABELLED: Current opinion is divided about the value of excisional surgery in Evans stage III neuroblastoma. AIMS: To evaluate and correlate the survival of patients with stage III neuroblastoma with the effectiveness of the surgical excision, as assessed by (1) the surgeon (resection data) at the time of operation and (2) the pathologist (excision data). METHODS: The ENSG (European Neuroblastoma Study Group) database of 202 patients from 29 centres with proven stage III were analysed. The data include all patients with neuroblastoma diagnosed between 1982 and 1992 and their subsequent follow-up. RESULTS: Patients were grouped according to the extent of resection (100%, 75% to 99%, and < 75%) and the completeness of excision (complete, microscopic residual, macroscopic residual). There were 123 with resection data, a subgroup of 104 with excision data, and 27 with no excision. There was no statistically significant difference (log rank test) in overall survival (p = 0.11) or event-free survival between the resection subgroups, even when the data from patients without resection were included. Complete excision was associated with a highly significant survival advantage, in terms of overall survival (P = .007) and event-free survival (P = .006). This effect is most obvious among patients with the worst prognosis: older children and those with an abdominal tumour. CONCLUSION: Histological confirmation of complete excision confers a significant survival advantage for patients with stage III neuroblastoma and justifies a painstaking attempt at complete resection.

Fibrinogen, factor VII clotting activity and coronary artery disease severity.

To asses the relationship between fibrinogen, factor VII coagulant (VIIc) activity and extent of coronary artery disease, we studied 43 white males shown to have greater than 50% stenosis of at least one major coronary artery. Thirty six had a definite history of myocardial infarction at least 3 months earlier and were classified as having 1, 2 or 3 vessel disease while 7 had 2 or 3 vessel disease, but no prior infarction. Groups were similar with regard to age, body mass index and blood pressure. In those with documented prior infarction, there was a significant relationship between the extent of atheroma and coagulation variables factor VIIc and fibrinogen. However, given a similar degree of atheroma, patients with prior infarction had significantly higher levels of factor VIIc activity compared with patients without such a history. These results corroborate those from prospective studies confirming a significant role for the coagulation system in the clinical manifestation of coronary artery disease.

Antithrombin III and procoagulant activity: sex differences and effects of the menopause.

Among participants in the Northwick Park Heart Study, antithrombin III activity was lower in pre-menopausal women than in men of the same age. In the women, however, the menopause was associated with a significant increase in antithrombin III, mean levels in these older women then exceeding levels in men of the same age. The occurrence of the menopause was also accompanied by large increases in factor VII coagulant activity, VIIc, and in plasma fibrinogen, these increases being greater in those experiencing a natural menopause than in those whose menopause was artificial. Sex differences in antithrombin III may form part of the explanation for the observed differences between men and women in their experience of ischaemic heart disease (IHD) and also for the contrasting effects of oral contraceptives and of hormone replacement therapy on the risk of thromboembolic disease.

Skinfold thickness, body mass index and ischaemic heart disease.

STUDY OBJECTIVE: To determine the relationship between obesity and subsequent incidence of ischaemic heart disease (IHD). DESIGN: Prospective cohort survey. SETTING: Study of three occupational groups, with follow up examinations. SUBJECTS: 3500 people recruited between 1972 and 1978 (80% response rate), and followed up between 1978 and 1984. This report is based on subgroup of 1511 white men aged 40-64 at entry. MEASUREMENTS AND MAIN RESULTS: Information was obtained on smoking and family history of IHD. Blood pressure, weight, height, skinfold thickness at four sites, fibrinogen, factor VII activity and cholesterol were measured during follow up. Body mass index (BMI) was used as an index of obesity. BMI was found to be more strongly correlated with IHD than any of the skinfold measurements, none of which was significantly associated with IHD when BMI was allowed for. Increase in BMI by 1 SD (approximately 8 kg) was associated with a 44% increase in the risk of IHD. Of the four skinfolds, subscapular was the most closely associated with risk, confirming the relevance of central obesity. The association between obesity and IHD remained when possible mechanisms for its effects were taken into account, and its strength may increase with time: for 1 SD increase in BMI, risk of events within 5 years was increased by 28%, while risk of events after longer than 5 years was increased by 65%. CONCLUSIONS: Preventive strategies for IHD should include avoidance of obesity.

Phobic anxiety and ischaemic heart disease.

A prospective study of the relation between scores on the six subscales of the Crown-Crisp experiential index and subsequent incidence of ischaemic heart disease was undertaken among participants in the Northwick Park heart study. Results from 1457 white men aged 40-64 at recruitment showed that phobic anxiety was strongly related to subsequent major ischaemic heart disease (fatal and non-fatal events combined) when other associated variables were taken into account. The phobic anxiety score alone remained significantly associated with ischaemic heart disease when scores on all the subscales were included in the analysis. Phobic anxiety seemed to be particularly associated with fatal ischaemic heart disease but was not associated with deaths from other causes and was no higher in those with a pre-existing myocardial infarction at recruitment than in those without. There was a consistent increase in risk of fatal ischaemic heart disease with score on the phobic anxiety subscale. The relative risk for those whose score was 5 and above was 3.77 (95% confidence interval 1.64 to 8.64) compared with those whose score was 0 or 1. The 49 participants with evidence of myocardial infarction at recruitment had higher scores on the subscales for free floating anxiety and functional somatic complaint. The Crown-Crisp experiential index is simple to fill out and acceptable to patients. When the results are combined with other known risk factors it may be of use in defining high risk subjects and in planning strategies for prevention.

Skinfold thickness and cardiovascular risk factors.

The relation of blood pressure, serum cholesterol, plasma fibrinogen, and coagulation factor VIIc with skinfold thickness at four sites (forearm, triceps, suprailiac, and subscapular) was examined in 2,948 white participants in the Northwick Park Heart Study. When considered separately, all four skinfolds were significantly associated with the four cardiovascular risk factors in males. Of the two limb skinfolds, forearm was consistently more strongly associated than triceps with the risk factors. The magnitude of the association between forearm skinfold and the risk factors was similar to that of the two trunk skinfolds, suprailiac and subscapular. Multiple regression analysis suggested an independent association of forearm skinfold with cholesterol and blood pressure in males when the other skinfolds were taken into account. There was no consistent difference in the strength of the associations of the two trunk skinfolds with the risk factors. With the exception of systolic blood pressure, the associations between the cardiovascular risk factors and skinfold thickness in males were stronger at younger ages. In the case of females the findings were somewhat different. The associations with the four risk factors were consistently stronger for the two trunk skinfolds than the limb skinfolds. Triceps was somewhat more strongly associated with the risk factors than forearm skinfold except for plasma fibrinogen. Thus there are sex differences in the association of the distribution of subcutaneous fat with cardiovascular risk factors.

Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study.

The Northwick Park Heart Study (NPHS) has investigated the thrombotic component of ischaemic heart disease (IHD) by the inclusion of measures of haemostatic function. Among 1511 white men aged between 40 and 64 at the time of recruitment, 109 subsequently experienced first major events of IHD. High levels of factor VII coagulant activity and of plasma fibrinogen were associated with increased risk, especially for events occurring within 5 years of recruitment. These associations seemed to be stronger than for cholesterol, elevations of one standard deviation in factor VII activity, fibrinogen, and cholesterol being associated with increases in the risk of an episode of IHD within 5 years of 62%, 84%, and 43% respectively. Multiple regression analyses indicated independent associations between each of the clotting factor measures and IHD but not between the blood cholesterol level and IHD incidence. The risk of IHD in those with high fibrinogen levels was greater in younger than in older men. Much of the association between smoking and IHD may be mediated through the plasma fibrinogen level. The biochemical disturbance leading to IHD may lie at least as much in the coagulation system as in the metabolism of cholesterol.

Effects of a fish oil supplement on platelet function, haemostatic variables and albuminuria in insulin-dependent diabetics.

A randomised trial of the effects of 15 gm per day of a fish oil supplement (MaxEPA) on blood lipids, haemostatic variables (including platelet function) and albuminuria was undertaken in 41 insulin dependent diabetics. Compared with the control group there was a significant reduction in thromboxane production by platelets stimulated by collagen in vitro in the group who took the fish oil supplement. The extent of platelet aggregation was not altered but the lag phase before aggregation was prolonged. There were also statistically significant increases in plasma LDL cholesterol, fibrinogen and clotting factor X in the group who took the fish oil supplement. No other significant differences were noted.

Blood pressure and the menstrual cycle.

A retrospective analysis of data from 207 non-pregnant premenopausal women showed that the mean level of systolic blood pressure varied with the stage of the menstrual cycle, being higher on days 17-26, the part of the luteal phase during which the peak of progestogen levels develops, than during the luteal phase as a whole, and significantly higher than the mean for all other days of the cycle. The mean levels were 125.4 mmHg (SE 1.76) for days 17-26, 122.5 (SE 1.25) for days 15-28 and 120.1 (SE 1.07) for days 1-16, 27 and 28. This finding supported the hypothesis that endogenous progestogen might have a hypertensive effect, as does exogenous progestogen. However, a second study designed to confirm this finding failed to do so, showing no cyclical change in the level of blood pressure. The subjects in the first study may have been subject to greater psychological stress when the measurements were made than were those in the second, a possibility supported by the large difference in pressure between the two studies. The discrepancy between the two sets of results could be explained if the effect possibly associated with progestogen levels in the retrospective study was due not to a hypertensive action per se but to a progestogen-related increased reaction to stress.

Relation of breath methane with obesity and other factors.

In a study of breath methane concentration 43 percent of males and 49 percent of females produced detectable amounts. The proportion of methane producers increased significantly with age in males but not in females. Obesity as measured by the sum of triceps, forearm, suprailiac and subscapular skinfolds was significantly less in producers than non-producers. Amongst methane producers there was also an inverse relationship between skinfold thickness and the breath methane concentration. Breath methane concentrations were lower in males than females. In addition, a higher proportion of methane producers was found amongst secretors of blood group substances (ABH antigen) than non-secretors.

The epidemiology of plasma renin.

1. The epidemiological characteristics of plasma renin activity (PRA) were established in 1999 members of occupational groups in North and West London. 2. The main finding was that PRA was inversely associated with systolic blood pressure in men, the percentage fall in PRA (on a log scale) being 8.4% for each increase of one standard deviation in systolic blood pressure. There was a less obvious inverse relationship in women. 3. However, blood pressure accounted for less than 1% of the variance in PRA. 4. Mean PRA in both smokers and ex-smokers was about 20% higher than in non-smokers. 5. PRA fell with increasing age, was lower in women than in men and considerably lower in blacks (of either sex) than whites. 6. PRA was lower in the first quarter of the menstrual cycle than in the rest of the cycle. 7. Haemoglobin, blood cholesterol, leucocyte count and Factor VIII were positively correlated with PRA. 8. PRA was lower in men with diagnosed hypertension than in those without; there was no significant difference in the women. 9. PRA was lower in those who had had myocardial infarcts in the past than in those who had not. 10. The data as a whole suggest that it may be low, not high, levels of PRA which are associated with increased risks of cardiovascular disease in which hypertension is a predisposing factor. 11. The explanation may be a homoeostatic fall in PRA in response to a rise in blood pressure rather than a major causal role for PRA in the pathogenesis of essential hypertension and target-organ damage.

Menopausal status and haemostatic variables.

The incidence of ischaemic heart disease (IHD) is higher in postmenopausal women than in premenopausal women of the same age. The difference may be partly explicable in terms of differences between premenopausal and postmenopausal women in haemostatic function. This possibility has been studied in 833 White women in the Northwick Park Heart Study (NPHS). Mean levels of factor VIIC, fibrinogen, and cholesterol were between 6% and 10% higher in postmenopausal women than in premenopausal women of the same age. When allowances were made for associations between these variables, the difference between the two groups in cholesterol was no longer evident. By analogy with NPHS data on men, the differences in factor VIIC, fibrinogen, and cholesterol would increase the risk of fatal IHD in postmenopausal women by about 40% compared with the risk in premenopausal women of the same age.

ABH secretor status and pulmonary function.

Among current cigarette smokers in the Northwick Park Heart Study in N.W. London, England, secretors of ABH antigen had a higher mean peak expiratory flow rate than did nonsecretors. The relationship was independent of other factors known to affect peak expiratory flow rate. No significant differences in peak expiratory flow rate by secretor status were detected in nonsmokers or in pipe and cigar smokers, although a smaller difference was seen among secretors and nonsecretors who were ex-cigarette smokers than among those who were current cigarette smokers. It is concluded that secretion of ABH antigen into the respiratory tract may have a protective effect against pulmonary damage by noxious agents.