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For most diseases there is considerable interest in the problem of classification, both in relation to medical diagnosis and for prognosis. Multivariate statistical methods are conventionally used as an aid to clinical decision making. Neural Networks (NNs) offer an alternative approach to this type of classification problem. Exploiting 1271 cases from the United Kingdom Medical Research Council UKALL X trial for childhood Acute Lymphoblastic Leukaemia (ALL), cases were stratified as ‘high risk’ or ‘standard risk’ using both the survival analysis technique of Cox Regression and trained neural networks. Based on 10 random trials with a further 300 cases, and predicting overall five year survival from age, sex and white cell count only, there was no significant difference between the two approaches in terms of mean Receiver Operating Characteristic area, though the regression model was slightly superior to a single neural network at high sensitivity (Wilcoxon signed rank test; p = 0.033). A composite of two networks, one of which included additional prognostic factors, restored the position of no significant difference. It was concluded that in the UKALL X dataset, factors predictive of outcome are fully described by a Cox regression analysis, and that a neural network-based analysis identified no additional prognostic features. The value of the network analysis lay in suggesting that the maximum amount of prognostic information has been extracted from the database.

Fanconi anemia (FA) is a rare autosomal recessive disorder characterized by congenital and developmental abnormalities, hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC), and strong predisposition to acute myeloid leukemia (AML). In this article, we describe clinical and molecular findings in a boy with a severe FA phenotype who developed AML by the age of 2. Although he lacked a strong family history of cancer, he was subsequently shown to carry biallelic mutations in the FANCD1/BRCA2 gene. These included an IVS7 splice-site mutation, which is strongly associated with early AML in homozygous or compound heterozygous carrier status in FA-D1 patients. Myeloid leukemia cells from this patient have been maintained in culture for more than 1 year and have been designated as the SB1690CB cell line. Growth of SB1690CB is dependent on granulocyte macrophage colony stimulating factor or interleukin-3. This cell line has retained its MMC sensitivity and has undergone further spontaneous changes in the spectrum of cytogenetic aberrations compared with the primary leukemia. This is the second AML cell line derived from an FA-D1 patient and the first proof that malignant clones arising in FA patients can retain inherited MMC sensitivity. As FA-derived malignancies are normally not very responsive to treatment, this implies there are important mechanisms of acquiring correction of the cellular FA phenotype that would explain the poor chemoresponsiveness observed in FA-associated malignancies and might also play a role in the initiation and progression of cancer in the general population.

The extent to which genetic susceptibility contributes to the causation of childhood acute myeloid leukaemia (AML) is not known. The inherited bone marrow failure disorder Fanconi anaemia (FA) carries a substantially increased risk of AML, raising the possibility that constitutional variation in the FA (FANC) genes is involved in the aetiology of childhood AML. We have screened genomic DNA extracted from remission blood samples of 97 children with sporadic AML and 91 children with sporadic acute lymphoblastic leukaemia (ALL), together with 104 cord blood DNA samples from newborn children, for variations in the Fanconi anaemia group C (FANCC) gene. We found no evidence of known FANCC pathogenic mutations in children with AML, ALL or in the cord blood samples. However, we detected 12 different FANCC sequence variants, of which five were novel to this study. Among six FANCC variants leading to amino-acid substitutions, one (S26F) was present at a fourfold greater frequency in children with AML than in the cord blood samples (odds ratio: 4.09, P = 0.047; 95% confidence interval 1.08-15.54). Our results thus do not exclude the possibility that this polymorphic variant contributes to the risk of a small proportion of childhood AML.

The aetiology of most childhood solid tumours (other than central nervous system [CNS] tumours) is unclear. To investigate whether certain environmental exposures may be involved, we have analysed for space-time clustering using population-based data from North West England for the period 1954-98. Knox tests for space-time interactions between cases were applied with fixed thresholds of close in space

In a previous study, we obtained preliminary evidence in a small series of patients (n = 63) suggesting that susceptibility to childhood common acute lymphoblastic leukaemia (c-ALL) was associated with an allele at the HLA-DPB1 locus, DPB1*0201. We have now tested this hypothesis by comparing the frequency of children with leukaemia (n = 982) who typed for specific DPB1 alleles and two groups of non-leukaemic children, one consisting of children with solid tumours, excluding lymphomas (n = 409), the other consisting of normal infants (n = 864). We found that significantly more children with c-ALL and T-ALL, but not pro-B ALL or acute non-ALL typed for DPB1*0201 as compared with children with solid tumours [odds ratio (OR), 95% confidence interval (CI) for c-ALL: 1.76, 1.20-2.56; T-ALL: 1.93, 1.01-3.80] and normal infants (OR, 95% CI for c-ALL: 1.83, 1.34-2.48; T-ALL: 2.00, 1.10-3.82). In childhood c-ALL, significantly more children than those with solid tumours or normal infants typed for DPB1 alleles coding specific polymorphic amino acids lining the antigen-binding site of the DPbeta1*0201 allotypic protein, suggesting that susceptibility to childhood c-ALL may be influenced by DPbeta ABS amino acid polymorphisms shared by DPbeta1*0201 and other DPbeta1 allotypes. These results point to a mechanism of c-ALL susceptibility that involves the presentation of specific antigenic peptides, possibly derived from infectious agents, by DPbeta1*0201-related allotypic proteins, leading to the activation of helper T cells mediating proliferative stress on preleukaemic cells.

To investigate whether infections or other environmental exposures may be involved in the aetiology of childhood central nervous system tumours, we have analysed for space–time clustering and seasonality using population-based data from the North West of England for the period 1954 to 1998. Knox tests for space–time interactions between cases were applied with fixed thresholds of close in space

BACKGROUND There has been speculation that increasing trends in incidence of childhood central nervous system tumors and infant neuroblastoma in the United States have been due to diagnostic improvements or reporting changes. To investigate whether or not such trends could be explained in this way in the U.K., the authors used population-based data from Northwest England to analyze incidence trends in childhood solid tumors. METHODS Cases were diagnosed during 1954–1998 and were grouped according to a morphology-based classification scheme. More than 95% of diagnoses were based on special histopathologic review. Tissue sections were retained, and diagnoses were rereviewed to ensure consistency in classification throughout the time period. Age-, gender- and period-specific incidence rates were calculated. Analyses were performed with chi-square tests and Poisson regression. RESULTS There was an overall increase in the incidence of all childhood solid tumors of 0.9% each year. A temporal increase was found in childhood brain tumors characterized by, in particular, annual increases of 1% in pilocytic astrocytoma, 1% in primitive neuroectodermal tumors, and 2.3% in miscellaneous gliomas. The incidence of germ cell tumors increased at a rate of 2.6% each year. CONCLUSIONS These increases could not be attributed to changes in diagnostic practice, and it is unlikely that the increases were due to changes in reporting practice. Further, the restriction of the increases to certain groups, with stable rates in others, argued against the changes being artifactual. The authors concluded that the increases in incidence were likely to be real. Cancer 2001;92:1967–76. © 2001 American Cancer Society.

The single most important prognostic determinant in childhood acute lymphoblastic leukaemia (ALL) is effective therapy and changes in therapy may influence the significance of other risk factors. The effect of intensified therapy on the importance of currently recognized phenotypic and genotypic determinants of outcome was assessed in 2090 children enrolled on the Medical Research Council United Kingdom acute lymphoblastic leukaemia XI (MRC UKALL XI) protocol. Treatment allocation was not determined by risk factors. Multivariate analysis confirmed the dominant influence on prognosis of age, sex and presenting white cell count (WCC). After allowing for these features, blast karyotype, d 8 marrow blast percentage and remission status at the end of induction therapy were the only remaining significant predictors of outcome. Organomegaly, haemoglobin concentration, French--American--British type, body mass index, presence of central nervous system disease at diagnosis, immunophenotype and presence of TEL/AML1 fusion gene (examined in a subset of 659 patients) either had no significant effect on outcome or were significant only in univariate analysis. Among karyotype abnormalities with an independent influence on prognosis, high hyperdiploidy (> 50 chromosomes) was shown to be favourable, whereas near haploidy (23--29 chromosomes), presence of the Philadelphia chromosome, t(4;11) and abnormalities affecting the short arm of chromosome 9 [abn (9p)] were adverse risk factors. Early responders to therapy, determined by residual marrow infiltration after 8 d of induction therapy, had a good outcome, while the small proportion of patients who did not achieve a complete remission by the end of induction therapy had a poor outcome. A third block of late intensification was shown to improve event-free survival by 8% at 5 years. The effect of these risk factors was not significantly different between those randomized to the third intensification block and those not randomized to a third block.

Low folate intake as well as alterations in folate metabolism as a result of polymorphisms in the enzyme methylenetetrahydrofolate reductase ( MTHFR ) have been associated with an increased incidence of neural tube defects, vascular disease, and some cancers. Polymorphic variants of MTHFR lead to enhanced thymidine pools and better quality DNA synthesis that could afford some protection from the development of leukemias, particularly those with translocations. We now report associations of MTHFR polymorphisms in three subgroups of pediatric leukemias: infant lymphoblastic or myeloblastic leukemias with MLL rearrangements and childhood lymphoblastic leukemias with either TEL - AML1 fusions or hyperdiploid karyotypes. Pediatric leukemia patients ( n = 253 total) and healthy newborn controls ( n = 200) were genotyped for MTHFR polymorphisms at nucleotides 677 (C→T) and 1,298 (A→C). A significant association for carriers of C677T was demonstrated for leukemias with MLL translocations ( MLL +, n = 37) when compared with controls [adjusted odd ratios (OR) = 0.36 with a 95% confidence interval (CI) of 0.15–0.85; P = 0.017]. This protective effect was not evident for A1298C alleles (OR = 1.14). In contrast, associations for A1298C homozygotes (CC; OR = 0.26 with a 95% CI of 0.07–0.81) and C677T homozygotes (TT; OR = 0.49 with a 95% CI of 0.20–1.17) were observed for hyperdiploid leukemias ( n = 138). No significant associations were evident for either polymorphism with TEL - AML1 + leukemias ( n = 78). These differences in allelic associations may point to discrete attributes of the two alleles in their ability to alter folate and one-carbon metabolite pools and impact after DNA synthesis and methylation pathways, but should be viewed cautiously pending larger follow-up studies. The data provide evidence that molecularly defined subgroups of pediatric leukemias have different etiologies and also suggest a role of folate in the development of childhood leukemia.

In the last 20 years, the survival rate for children with acute lymphoblastic leukaemia (ALL) has markedly improved, largely owing to a decrease in relapses. However, children still die from complications of treatment and these are potentially preventable. We have analysed data from three large consecutive national protocols for ALL from 1980 to 1997 [Medical Research Council United Kingdom ALL (MRC UKALL) trials VIII, X and XI] to compare the incidence and causes of treatment-related deaths (TRD). The percentage of TRD has fallen from 9% to 2% (UKALL VIII to XI), largely as a result of a decrease in fatal infections. Deaths during induction have fallen from 3% to 1%, the main causes of death being bacterial, followed by fungal infection, while other causes, chiefly haemorrhage, have not declined. Remission deaths also decreased from 6% to 1%, particularly those deaths due to measles and pneumocystis carinii. More guidelines for surveillance and treatment of infections have been included within progressively more intensive protocols. Risk factor analysis showed increased TRD in patients with Down's syndrome, high leucocyte count and older age in UKALL XI. In contrast, the introduction of blocks of intensification was not associated with an increased death rate. While improved supportive care has reduced the incidence of TRD, there is still scope for further reduction by prompt treatment of suspected infection. Maintenance of herd immunity remains of vital importance in avoiding deaths from measles.

We have examined the toxicity and overall outcome of the Medical Research Council UKALL R1 protocol for 256 patients with relapsed childhood acute lymphoblastic leukaemia (ALL). Second remission was achieved in over 95% of patients. Two patients died during induction and seven patients died of resistant disease. The overall actuarial event-free survival (EFS) at 5 years for all patients experiencing a first relapse was 46% (95% CI 40-52). Duration of first remission, site of relapse, age at diagnosis and sex emerged as factors of prognostic significance. Five-year EFS was only 7% for children relapsing in the bone marrow within 2 years of diagnosis, but was 77% for those relapsing without bone marrow involvement > 2.5 years from diagnosis. All analyses in this report are by treatment received. For those receiving chemotherapy alone, the 5-year EFS was 48%; for autologous bone marrow transplantation (BMT), the 5-year EFS was 47%; for unrelated donor BMT, it was 52%; and for related donor BMT, the 5-year EFS was 45%. The groups, however, were not comparable with respect to risk factor profile, and therefore direct comparison of EFS is misleading. Adjustment for time to transplant and prognostic factors was used to reduce the effects of biases between treatment groups, but did not suggest benefit for any particular treatment. There was failure of our planned randomization scheme in this trial with only 9% of those eligible being randomized, which highlights the difficulties in running randomized trials especially in patients who have relapsed from a previous trial. The optimal treatment for relapsed ALL therefore remains uncertain. Alternative approaches are clearly needed for those with early bone marrow relapse if outcome is to improve.

BACKGROUND Malignant melanoma (MM) is one of the least common types of childhood cancer, accounting for less than 1% of all pediatric malignancies. Neurocutaneous melanosis (NCM) is a rare phakomatosis consisting of congenital abnormal pigmentation of the skin and meninges. The meningeal lesions are particularly prone to malignant change. METHODS The authors describe 5 patients with NCM and 1 with primary leptomeningeal melanoma (LMM) seen at 2 treatment centers in the north of England over a 13-year period (1984–1997). RESULTS The clinical features, progress, radiological findings, and treatment of these patients are discussed. All six died within eight months of their diagnosis, illustrating the difficulties faced in treating patients with these conditions. The authors reviewed the published literature on NCM, concentrating on the various therapeutic strategies that have been tried. Very little consistency in approach was found. Malignant skin lesions in NCM may be less responsive than primary malignant melanoma, but the small number of patients with primary LMM or brain metastases of MM make comparisons with NCM difficult. The authors' own series illustrates well the piecemeal nature of therapy for patients with these rare conditions. CONCLUSIONS The rate of incidence of MM melanoma in the U.K. is increasing, and it will represent an increasing proportion of the pediatric oncologist's workload. A consistent approach to the therapy of patients with metastatic MM and NCM is needed if we are to have any hope of offering more than palliative therapy to these children in the future. Cancer 1999;86:878–86. © 1999 American Cancer Society.

Previous serological studies documenting an association between acute lymphoblastic leukaemia (ALL) and HLA-Cw antigens suggested that the HLA-C locus might influence susceptibility to ALL. However, associations with more than one Cw antigen suggest that polymorphic variants shared by more than Cw allele could be involved. Recent studies have shown that the HLA-C locus encodes two ligands (NK1 and NK2) recognized by receptors on natural killer (NK) cells. HLA-Cw alleles encoding these ligands are dimorphic, dependent on whether they encode one or other NK ligand. To determine whether susceptibility to the common (CD10+) form of childhood ALL (c-ALL) is associated with NK1 or NK2, we carried out a molecular analysis of 94 childhood c-ALL patients and 136 infant controls. We found no difference in the frequency of NK1 and NK2 alleles, phenotypes or genotypes between the patients and controls, suggesting that this does not explain the role of the HLA-C locus in susceptibility to childhood c-ALL.

Infection has long been suspected as a possible factor in the aetiology of leukaemia and lymphoma. If seasonal variation in the onset of disease could be shown in any of the diagnostic subgroups of leukaemia or lymphoma, this would provide supportive evidence of an aetiology linked to exposure to infection. All cases in the Manchester Children's Tumour Registry (aged 0-14 years at diagnosis) with acute lymphoblastic leukaemia (ALL), acute non-lymphocytic leukaemia (ANLL), Hodgkin's disease (HD) or non-Hodgkin lymphoma (NHL) between 1 January 1954 and 31 December 1996 were included in an analysis of seasonal variation in the month of first symptom and the month of diagnosis. Cases of common acute lymphoblastic leukaemia (c-ALL) diagnosed from 1979 onwards were also analysed separately. The groups considered for analysis were: all cases of ALL (n = 1070), ALL diagnosed between 18 and 95 months of age (n = 730), ALL diagnosed over 95 months of age (n = 266), c-ALL (n = 309), ANLL (n = 244), all infant acute leukaemias (ALL and ANLL under 18 months; n = 107), HD (n = 166) and NHL (n = 189). Using the Edwards method, both c-ALL and HD demonstrated significant seasonal variation (P = 0.037 and 0.001 respectively) in date of first symptom, with peaks occurring in November and December respectively. Using this method, no indication of seasonal variation was found in the other diagnostic groups for date of first symptom or in any of the diagnostic groups for date of diagnosis. For comparison with a previous study, a further analysis based on date of diagnosis for all ALL cases, using summer-winter ratios, showed a significant summer excess. These results provide supportive evidence for an infectious aetiology for c-ALL and HD, and possibly for all ALL, which warrants further investigation.

Treatment-related acute myeloid leukaemia (t-AML) is a serious complication of topoisomerase 2 inhibitor therapy and is characterised by the presence of mixed lineage leukaemia (MLL) rearrangement. By molecular tracking, we were able to show that MLL cleavage preceded gene rearrangement by 3 months and before the clinical diagnosis of t-AML in a patient with haemophagocytic lymphohistiocytosis. This is the first report on the sequential detection of the two biomarkers in treatment-related leukaemogenesis.

Concern about late adverse effects of cranial radiotherapy (XRT) has led to alternative approaches to eliminate leukaemia from the central nervous system (CNS) in childhood acute lymphoblastic leukaemia (ALL). The Medical Research Council UKALL XI trial recruited 2090 children with ALL between 1990 and 1997. Median follow-up is 7 years 9 months; event-free survival (EFS) and overall survival were 63.1% and 84.6%, respectively, at 5 years and 59.8% and 79.4% at 10 years. The isolated CNS relapse rate was 7.0% at 10 years. Patients were randomized for CNS-directed therapy within white blood cell (WBC) groups. For WBC /=50 x 10(9)/l, HDMTX with ITMTX was compared with XRT and a short course of ITMTX. CNS relapses were significantly fewer with XRT, but there was a non-significant increase in non-CNS relapses. EFS was not significantly different, being 55.2% (95% CI 47.8-62.6) at 10 years with XRT and 52.1% (95% CI 44.8-59.4) with HDMTX plus ITMTX.

Childhood leukaemias and lymphomas have been associated with exposure to environmental factors, including infections, which show geographical variation. This study examined the geographical distribution of the incidence of acute leukaemia and lymphoma using Manchester Children's Tumour Registry (MCTR) data 1976-2000. A total of 910 children were included, all of whom had histologically and/or cytologically verified leukaemia or lymphoma. At the time of their diagnoses, all the children were aged 0-14 years and were resident in the counties of Greater Manchester or Lancashire. Standardized morbidity ratios were calculated. Poisson regression was used to examine the relationship between incidence rates and small-area (census ward) population density, ethnic composition and deprivation index. There was a monotonic relationship between acute lymphoblastic leukaemia (ALL) incidence and population density (P = 0.05). Higher rates were seen in more densely populated areas. There was evidence for a monotonic relationship between the incidence of the mixed cellularity subtype of Hodgkin's disease (HD) and the Townsend deprivation score (P = 0.001). Markedly higher incidence was associated with greater levels of unemployment and household overcrowding. The results for ALL and mixed cellularity HD support the involvement of environmental factors, such as infections, in disease aetiology.

The aim of this paper was to study the geographical distribution of Wilms' tumours (WT) and soft-tissue sarcomas (STS) for 0-14 year olds included in a population-based registry from North West England during 1976-2000. Standardised morbidity ratios (SMRs) were calculated. Relationships between incidence rates and small area (ward) population density, ethnic composition, deprivation index and urban-rural status were examined using Poisson regression. There was a non-linear relationship between WT incidence and population density (P=0.008), with a higher incidence associated with wards with low deprivation scores (P=0.02); and which included a greater proportion of whites (P=0.01). For STS, a higher incidence was associated with wards with low deprivation scores (P=0.04); and which were 'more rural/less urban' (P=0.03). These results are consistent with a role for localised environmental exposures, in combination with lifestyle factors, in the aetiology of WT. For STS, there is some evidence for the involvement of environmental and/or lifestyle factors.

Adult survivors of childhood cancer have impaired psychosocial functioning, but not much is known about the causes. In this study we examined the role of relationships with parents as a possible mediating factor.One hundred and two adult survivors (82% of those eligible, 35 female and 57 male) of childhood Acute Lymphoblastic Leukaemia and Wilms' Tumour, and 102 matched controls (74% of those eligible) aged 19-30 were interviewed. Interpersonal and social role functioning, and current relationships with each parent were assessed in standardised investigator-based interviews with subjects.Adult survivors were more likely than controls to have impaired close relationships (love relationships and friendships), and poorer day-to-day coping. Lower encouragement from fathers and greater involvement with mothers were each independently associated with impaired close relationships outside the family. This association was evident across the sample and in the cancer survivor group. It was much stronger in young adult females. Lower paternal encouragement was also associated with poor day-to-day coping, and this association was stronger in young men. There was, however, little evidence that quality of relationships with parents mediated the link between childhood cancer and adult psychosocial functioning.Within this cross-sectional design we could not determine the direction of influence, nor exclude third variable effects. However, the findings indicate that mothers and fathers have different roles in the transition to adult life, and understanding these may assist the development of interventions designed to improve adult psychosocial functioning.

The extent to which genetic susceptibility contributes to the causation of childhood acute myeloid leukaemia (AML) is not known. The inherited bone marrow failure disorder Fanconi anaemia (FA) carries a substantially increased risk of AML, raising the possibility that constitutional variation in the FA (FANC) genes is involved in the aetiology of childhood AML. We have screened genomic DNA extracted from remission blood samples of 97 children with sporadic AML and 91 children with sporadic acute lymphoblastic leukaemia (ALL), together with 104 cord blood DNA samples from newborn children, for variations in the Fanconi anaemia group C (FANCC) gene. We found no evidence of known FANCC pathogenic mutations in children with AML, ALL or in the cord blood samples. However, we detected 12 different FANCC sequence variants, of which five were novel to this study. Among six FANCC variants leading to amino-acid substitutions, one (S26F) was present at a fourfold greater frequency in children with AML than in the cord blood samples (odds ratio: 4.09, P = 0.047; 95% confidence interval 1.08-15.54). Our results thus do not exclude the possibility that this polymorphic variant contributes to the risk of a small proportion of childhood AML.

The occurrence of childhood acute lymphoblastic leukemia (ALL) in 2 of 3 triplets provided a unique opportunity for the investigation of leukemogenesis and the natural history of ALL. The 2 leukemic triplets were monozygotic twins and shared an identical, acquiredTEL-AML1 genomic fusion sequence indicative of a single-cell origin in utero in one fetus followed by dissemination of clonal progeny to the comonozygotic twin by intraplacental transfer. In accord with this interpretation, clonotypic TEL-AML1 fusion sequences could be amplified from the archived neonatal blood spots of the leukemic twins. The blood spot of the third, healthy, dizygotic triplet was also fusion gene positive in a single segment, though at age 3 years, his blood was found negative by sensitive polymerase chain reaction (PCR) screening for the genomic sequence and by reverse transcription–PCR. Leukemic cells in both twins had, in addition toTEL-AML1 fusion, a deletion of the normal, nonrearrangedTEL allele. However, this genetic change was found by fluorescence in situ hybridization to be subclonal in both twins. Furthermore, mapping of the genomic boundaries of TELdeletions using microsatellite markers indicated that they were individually distinct in the twins and therefore must have arisen as independent and secondary events, probably after birth. These data support a multihit temporal model for the pathogenesis of the common form of childhood leukemia.

The spectrum and frequency of cancers associated with germline TP53 mutations are uncertain. To address this issue a cohort of individuals from 28 families with Li-Fraumeni syndrome, segregating germline TP53 mutations was established. Predicted cancers were estimated by applying age, morphology, site and sex-specific UK cancer statistics to person-years at risk. Observed and predicted cancers were compared and two-sided P-values calculated. Cancer types occurring to excess and showing P-values

A temporal increase in the incidence of childhood acute lymphoblastic leukaemia (ALL) in the UK has been noted. We present data from the Manchester Children's Tumour Registry which provide strong evidence that the increase is a result of an increase in the precursor B-cell subtype. In the childhood peak (age 1-4 years), the annual increase in precursor B-cell ALL between 1980 and 1998 was 3.0% (p=0.024). Recent findings are consistent with the causal involvement of infections in precursor B-cell ALL.

Twenty new cases of acute lymphoblastic leukemia (ALL) with the dicentric chromosome dic(9;20)(p1113;q11) are presented. This chromosomal abnormality is difficult to identify from G-banding alone. It masquerades as monosomy 20 and is only accurately identified by fluorescence in situ hybridization (FISH). Monosomy 20 was found in 59/2790 patients with successful karyotypes entered to the Leukaemia Research Fund/UK Cancer Cytogenetics Group Karyotype Database in ALL (LRF/UKCCG Karyotype Database). FISH revealed dic(9;20) in 20/25 cases with available material. Extra copies of chromosome 21 were found in 8 of the 20 cases. Patients were 14 females and six males, aged 1-32 years (median 4 years), with leukocyte counts of 2-536 (median 23) x 109/l and immunophenotypes of common or pre-B ALL (17 cases), T-ALL (one case) or unknown (two cases). Four patients relapsed at 2, 22, 28 and 47 months and two died at 49 and 63 months (median follow-up 37 months). FISH studies on the remaining five patients showed one with monosomy 20 and four with other rearrangements of the chromosome. This study has increased the number of reported cases of dic(9;20) from 17 to 37. It has identified dic(9;20) in one case of T-ALL and shows an association of this translocation with trisomy 21.

OBJECTIVES—To review the outcome of patients with childhood malignancy requiring intensive care treatment and to assess whether there is any secular trend for improved outcome. DESIGN—Retrospective chart reviews of 74 consecutive admissions to a paediatric intensive care unit from a regional paediatric oncology centre between 1990 and 1997. During the same period there were 6419 admissions to the oncology unit, 814 of whom were new cases. RESULTS—The overall survival at discharge from the intensive care unit was 49 of 74. Patients with either systemic or respiratory infection requiring ventilation had the poorest survival (13 of 31) whereas postoperative patients had the best survival (15 of 15). However, patients with respiratory or systemic infection who required inotropic support with more than three agents all died compared with about one quarter of those needing no inotrope. All patients with systemic or respiratory infective illness were neutropenic and positive microbiological identification was possible in 13 of 21 and five of 18, respectively. Non-survivors had a higher mean acute physiology and chronic health evaluation system (APACHE-II) score than survivors (24.2 v 15.94, respectively) but no patient with a score of > 27 survived. CONCLUSION—Compared with previous series, there has been a great improvement in survival of oncology patients admitted to the intensive care unit especially those with either systemic or respiratory infection needing ventilation. Full intensive care treatment should be provided for these patients.

Comparison of DQA1 and DQB1 alleles in 60 children with common acute lymphoblastic leukaemia (c-ALL) and 78 newborn infant control subjects revealed that male but not female patients had a higher frequency of DQA1*0101/*0104 and DQB1*0501 than appropriate control subjects. The results suggest a male-associated susceptibility haplotype in c-ALL and supports an infectious aetiology.

Epidemiological evidence has suggested that some pediatric leukemias may be initiated in utero and, for some pairs of identical twins with concordant leukemia, this possibility has been strongly endorsed by molecular studies of clonality. Direct evidence for a prenatal origin can only be derived by prospective or retrospective detection of leukemia-specific molecular abnormalities in fetal or newborn samples. We report a PCR-based method that has been developed to scrutinize neonatal blood spots (Guthrie cards) for the presence of numerically infrequent leukemic cells at birth in individuals who subsequently developed leukemia. We demonstrate that unique or clonotypic MLL-AF4 genomic fusion sequences are present and detectable in neonatal blood spots from individuals who were diagnosed with acute lymphoblastic leukemia at ages 5 months to 2 years and, therefore, have arisen during fetal hematopoiesis in utero . This result provides unequivocal evidence for a prenatal initiation of acute leukemia in young patients. The method should be applicable to other fusion genes in children with common subtypes of leukemia and will be of value in attempts to unravel the natural history and etiology of this major subtype of pediatric cancer.

We studied the influence of patient, leukaemia and treatment characteristics on the kinetics of Minimal Residual Disease (MRD) clearance in children with lymphoblastic leukaemia treated using an intensive risk stratified approach. UK MRC protocol ALL97 (1997–1999), and its amended version ALL 97/99 (1999–2002), compared the efficacy and toxicity of dexamethasone (DEX) with prednisolone (PRED), and 6-thioguanine (TG) with 6-Mercaptopurine (MP) in a randomised fashion. The trial produced a 5 year event-free survival (EFS) of 80%, with better systemic and Central Nervous System outcomes in DEX compared with PRED recipients but no difference between TG and MP recipients. Several changes to the risk stratification and treatment regimens during the period of the trial provided an opportunity to determine their impact on MRD clearance. We compared this with clearance in those treated on the successor trial ALL 2003 (more intensive induction containing DEX and Pegylated Asparaginase). The variables investigated for their potential influence on MRD status at the end of induction (EOI) were: NCI Risk; Asparaginase intensity (Erwinia Asparaginase [ERW] in ALL 97 and early part of ALL97/99 vs native or Pegylated E. Coli Asparaginase [E. Coli] in later part of ALL 97/99 and ALL2003); DEX vs PRED; and marrow response at day 8/15 of induction (Slow Early Response [SER] >25% blasts vs Rapid Early Response [RER] ⩽ 25% blasts). MRD was assessed using either a semi-quantitative sequence-specific PCR (ALL97) or Real-Time Quantitative PCR (ALL99 and ALL 2003) of antigen receptor gene re-arrangements at EOI. MRD status was defined as NEG if no MRD was detected by two markers sensitive to 10−4; POS if > 10−4, and Positive Outside Quantitative Range (POQR) if positive < 10−4. Results were available from retrospective testing in 66 ALL97 and 76 ALL97/99 patients, and 204 ALL2003 patients monitored prospectively. There was no significant difference in the proportions of patients MRD NEG, POS or POQR in steroid or NCI sub-groups. Significantly more ERW Asparaginase recipients were MRD POS compared with E.Coli (p< 0.0005). Although SER was predictive of slow MRD clearance, 80/235 (34%) RERs were MRD POS and 9/27(33%) SERs were MRD NEG. Relapse risk at 4 years is 8% in NEG v 28% in POS group in ALL97, 0% in NEG/POQR, versus 15% in POS group in ALL97/99 (p=.001) 2 of the ALL2003 patients have relapsed; one was POS and the other POQR. In the context of intensive risk stratified treatment of childhood ALL, type of Asparaginase influenced rapidity of MRD clearance, whilst NCI risk and type of steroid had no significant influence. Patients with detectable MRD < 10−4 at EOI have the same low risk of relapse as those who have undetectable MRD.

A 4-yr-old boy with acute lymphoblastic leukaemia in remission developed an encephalopathy following an attenuated measles infection. He was treated with interferon and further deterioration was halted. Three weeks after interferon treatment was stopped, leukaemic blast cells reappeared in his peripheral blood and he died shortly thereafter. Aspects of diagnosis and treatment of this syndrome are discussed now that the presumptive clinical diagnosis is made more frequently.