Prenatal origin of childhood AML occurs less frequently than in childhood ALL

Background While there is enough convincing evidence in childhood acute lymphoblastic leukemia (ALL), the data on the pre-natal origin in childhood acute myeloid leukemia (AML) are less comprehensive. Our study aimed to screen Guthrie cards (neonatal blood spots) of non-infant childhood AML and ALL patients for the presence of their respective leukemic markers. Methods We analysed Guthrie cards of 12 ALL patients aged 2–6 years using immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements (n = 15) and/or intronic breakpoints of TEL/AML1 fusion gene (n = 3). In AML patients (n = 13, age 1–14 years) PML/RARalpha (n = 4), CBFbeta/MYH11 (n = 3), AML1/ETO (n = 2), MLL/AF6 (n = 1), MLL/AF9 (n = 1) and MLL/AF10 (n = 1) fusion genes and/or internal tandem duplication of FLT3 gene (FLT3/ITD) (n = 2) were used as clonotypic markers. Assay sensitivity determined using serial dilutions of patient DNA into the DNA of a healthy donor allowed us to detect the pre-leukemic clone in Guthrie card providing 1–3 positive cells were present in the neonatal blood spot. Results In 3 patients with ALL (25%) we reproducibly detected their leukemic markers (Ig/TCR n = 2; TEL/AML1 n = 1) in the Guthrie card. We did not find patient-specific molecular markers in any patient with AML. Conclusion In the largest cohort examined so far we used identical approach for the backtracking of non-infant childhood ALL and AML. Our data suggest that either the prenatal origin of AML is less frequent or the load of pre-leukemic cells is significantly lower at birth in AML compared to ALL cases

Spectrum of HLA associations: the case of medically refractory pediatric acute lymphoblastic leukemia

Although studies of HLA and disease now date back some 50 years, a principled understanding of that relationship has been slow to emerge. Here, we examine the associations of three HLA loci with medically refractory pediatric acute lymphoblastic leukemia (pALL) patients in a case–control study involving 2,438 cases and 41,750 controls. An analysis of alleles from the class I loci, HLA-A and HLA-B, and the class II locus DRB1 illuminates a spectrum of extremely significant allelic associations conferring both predisposition and protection. Genotypes constructed from predisposing, protective, and neutral allelic categories point to an additive mode of disease causation. For all three loci, genotypes homozygous for predisposing alleles are at highest disease risk while the favorable effect of homozygous protective genotypes is less striking. Analysis of A–B and B–DRB1 haplotypes reveals locus-specific differences in disease effects, while that all three loci influence pALL; the influence of HLA-B is greater than that of HLA-A, and the predisposing effect of DRB1 exceeds that of HLA-B. We propose that the continuum in disease susceptibility suggests a system in which many alleles take part in disease predisposition based on differences in binding affinity to one or a few peptides of exogenous origin. This work provides evidence that an immune response mediated by alleles from several HLA loci plays a critical role in the pathogenesis of pALL, adding to the numerous studies pointing to a role for an infectious origin in pALL

Factors associated with study attrition in a pilot randomised controlled trial to explore the role of exercise-assisted reduction to stop (EARS) smoking in disadvantaged groups.

BACKGROUND: Study attrition has the potential to compromise a trial's internal and external validity. The aim of the present study was to identify factors associated with participant attrition in a pilot trial of the effectiveness of a novel behavioural support intervention focused on increasing physical activity to reduce smoking, to inform the methods to reduce attrition in a definitive trial. METHODS: Disadvantaged smokers who wanted to reduce but not quit were randomised (N = 99), of whom 61 (62 %) completed follow-up assessments at 16 weeks. Univariable logistic regression was conducted to determine the effects of intervention arm, method of recruitment, and participant characteristics (sociodemographic factors, and lifestyle, behavioural and attitudinal characteristics) on attrition, followed by multivariable logistic regression on those factors found to be related to attrition. RESULTS: Participants with low confidence to quit, and who were undertaking less than 150 mins of moderate and vigorous physical activity per week at baseline were less likely to complete the 16-week follow-up assessment. Exploratory analysis revealed that those who were lost to follow-up early in the trial (i.e., by 4 weeks), compared with those completing the study, were younger, had smoked for fewer years and had lower confidence to quit in the next 6 months. Participants who recorded a higher expired air carbon monoxide reading at baseline were more likely to drop out late in the study, as were those recruited via follow-up telephone calls. Multivariable analyses showed that only completing less than 150 mins of physical activity retained any confidence in predicting attrition in the presence of other variables. CONCLUSIONS: The findings indicate that those who take more effort to be recruited, are younger, are heavier smokers, have less confidence to quit, and are less physically active are more likely to withdraw or be lost to follow-up

Association of childhood acute lymphoblastic leukaemia with cancers in family members

Children whose twins have had leukaemia have a higher risk of contracting acute lymphoblastic leukaemia (ALL), confirming a prenatal origin of the disease. This association was not true when considering other types of affected first-degree relatives. Children whose fathers were diagnosed with testicular cancer have a higher risk of ALL

An Exploratory Analysis of the Smoking and Physical Activity Outcomes From a Pilot Randomized Controlled Trial of an Exercise Assisted Reduction to Stop Smoking Intervention in Disadvantaged Groups.

INTRODUCTION: Economically disadvantaged smokers not intending to stop may benefit from interventions aimed at reducing their smoking. This study assessed the effects of a behavioral intervention promoting an increase in physical activity versus usual care in a pilot randomized controlled trial. METHODS: Disadvantaged smokers who wanted to reduce but not quit were randomized to either a counseling intervention of up to 12 weeks to support smoking reduction and increased physical activity (n = 49) or usual care (n = 50). Data at 16 weeks were collected for various smoking and physical activity outcomes. Primary analyses consisted of an intention to treat analysis based on complete case data. Secondary analyses explored the impact of handling missing data. RESULTS: Compared with controls, intervention smokers were more likely to initiate a quit attempt (36 vs. 10%; odds ratio 5.05, [95% CI: 1.10; 23.15]), and a greater proportion achieved at least 50% reduction in cigarettes smoked (63 vs. 32%; 4.21 [1.32; 13.39]). Postquit abstinence measured by exhaled carbon monoxide at 4-week follow-up showed promising differences between groups (23% vs. 6%; 4.91 [0.80; 30.24]). No benefit of intervention on physical activity was found. Secondary analyses suggested that the standard missing data assumption of "missing" being equivalent to "smoking" may be conservative resulting in a reduced intervention effect. CONCLUSIONS: A smoking reduction intervention for economically disadvantaged smokers which involved personal support to increase physical activity appears to be more effective than usual care in achieving reduction and may promote cessation. The effect does not appear to be influenced by an increase in physical activity

Altered Time Awareness in Dementia

Our awareness of time, specifically of longer intervals spanning hours, days, months, and years, is critical for ensuring our sense of self-continuity. Disrupted time awareness over such intervals is a clinical feature in a number of frontotemporal dementia syndromes and Alzheimer's disease, but has not been studied and compared systematically in these diseases. We used a semi-structured caregiver survey to capture time-related behavioral alterations in 71 patients representing all major sporadic and genetic syndromes of frontotemporal dementia, in comparison to 28 patients with typical Alzheimer's disease and nine with logopenic aphasia, and 32 healthy older individuals. Survey items pertained to apparent difficulties ordering past personal events or estimating time intervals between events, temporal rigidity and clockwatching, and propensity to relive past events. We used a logistic regression model including diagnosis, age, gender, and disease severity as regressors to compare the proportions of individuals exhibiting each temporal awareness symptom between diagnostic groups. Gray matter associations of altered time awareness were assessed using voxel-based morphometry. All patient groups were significantly more prone to exhibit temporal awareness symptoms than healthy older individuals. Clinical syndromic signatures were identified. While patients with typical and logopenic Alzheimer's disease most frequently exhibited disturbed event ordering or interval estimation, patients with semantic dementia were most prone to temporal rigidity and clockwatching and those with behavioral variant frontotemporal dementia commonly exhibited all these temporal symptoms as well as a propensity to relive past events. On voxel-based morphometry, the tendency to relive past events was associated with relative preservation of a distributed left-sided temporo-parietal gray matter network including hippocampus. These findings reveal a rich and complex picture of disturbed temporal awareness in major dementia syndromes, with stratification of frontotemporal dementia syndromes from Alzheimer's disease. This is the first study to assess symptoms of altered temporal awareness across frontotemporal dementia syndromes and provides a motivation for future work directed to the development of validated clinical questionnaires, analysis of underlying neurobiological mechanisms and design of interventions

Presence of clone-specific markers at birth in children with acute lymphoblastic leukaemia

Recent studies have suggested that development of childhood acute lymphoblastic leukaemia may often be initiated in utero. To provide further evidence of an prenatal origin of childhood leukaemia, we conducted a molecular biological investigation of nine children with B-precursor acute lymphoblastic leukaemia carrying the chromosomal translocation t(12;21), the most common subtype of all childhood acute lymphoblastic leukaemia. Specifically, for each child we identified the non-constitutive chromosomal sequences made up by the t(12;21) fusion gene. From these, leukaemia clone-specific DNA primers were constructed and applied in nested polymerase chain reaction analyses of DNA extracted from the patients' Guthrie cards obtained at birth. Leukaemia clone-specific fusion gene regions were demonstrated in Guthrie card DNA of three patients, age 2 years 11 months, 3 years 4 months, and 5 years 8 months at leukaemia diagnosis. Our findings are consistent with previous observations, and thus provide further evidence that the development of t(12;21) B-precursor acute lymphoblastic leukaemia may be initiated in utero. Review of the current literature moreover indicates that age at leukaemia may be inversely correlated with the burden of cells with leukaemia clonal markers, i.e. leukaemia predisposed cells at birth, and that certain types of childhood acute lymphoblastic leukaemia develop as a multiple step process involving both pre- and postnatal genetic events

Simultaneous localization of MLL, AF4 and ENL genes in interphase nuclei by 3D-FISH: MLL translocation revisited

BACKGROUND: Haematological cancer is characterised by chromosomal translocation (e.g. MLL translocation in acute leukaemia) and two models have been proposed to explain the origins of recurrent reciprocal translocation. The first, established from pairs of translocated genes (such as BCR and ABL), considers the spatial proximity of loci in interphase nuclei (static "contact first" model). The second model is based on the dynamics of double strand break ends during repair processes (dynamic "breakage first" model). Since the MLL gene involved in 11q23 translocation has more than 40 partners, the study of the relative positions of the MLL gene with both the most frequent partner gene (AF4) and a less frequent partner gene (ENL), should elucidate the MLL translocation mechanism. METHODS: Using triple labeling 3D FISH experiments, we have determined the relative positions of MLL, AF4 and ENL genes, in two lymphoblastic and two myeloid human cell lines. RESULTS: In all cell lines, the ENL gene is significantly closer to the MLL gene than the AF4 gene (with P value < 0.0001). According to the static "contact first" model of the translocation mechanism, a minimal distance between loci would indicate a greater probability of the occurrence of t(11;19)(q23;p13.3) compared to t(4;11)(q21;q23). However this is in contradiction to the epidemiology of 11q23 translocation. CONCLUSION: The simultaneous multi-probe hybridization in 3D-FISH is a new approach in addressing the correlation between spatial proximity and occurrence of translocation. Our observations are not consistent with the static "contact first" model of translocation. The recently proposed dynamic "breakage first" model offers an attractive alternative explanation

Association of early life factors and acute lymphoblastic leukaemia in childhood: historical cohort study

In a historical cohort study of all singleton live births in Northern Ireland from 1971–86 (n=434 933) associations between early life factors and childhood acute lymphoblastic leukaemia were investigated. Multivariable analyses showed a positive association between high paternal age (⩾35 years) and acute lymphoblastic leukaemia (relative risk=1.49; 95% confidence interval (CI)=0.96–2.31) but no association with maternal age. High birth weight (⩾3500 g) was positively associated with acute lymphoblastic leukaemia (relative risk=1.66; 95% CI=1.18–2.33). Children of mothers with a previous miscarriage or increased gestation (⩾40 weeks) had reduced risks of ALL (respective relative risks=0.49; 95% CI=0.29–0.80, and 0.67; 95% CI=0.48–0.94). Children born into more crowded households (⩾1 person per room) had substantially lower risks than children born into less crowded homes with also some evidence of a lower risk for children born into homes with three adults (relative risks=0.56; 95% CI=0.35–0.91 and 0.58; 95% CI=0.21–1.61 respectively). These findings indicate that several early life factors, including living conditions in childhood and maternal miscarriage history, influence risk of acute lymphoblastic leukaemia in childhood