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Introduction TET2, a member of the Ten-Eleven translocation gene family, catalyzes the conversion of 5-methylcytosine to 5-hydroxymethylcytosine in DNA. Low expression of TET2 has been reported as a prognostic factor for several types of malignancies in adult patients. However, there have been few data on the effect of TET2 mRNA level on the prognosis of children with ALL so far. Methods In this study, TET2 expression of samples cryopreserved in the liquid nitrogen from January 1, 2007 through December 31, 2011 was retrospectively analyzed in 136 newly diagnosed ALL patients by real-time polymerase chain reaction (PCR) assay. The patients' samples were divided into two groups by the median value of patients group and divided into TET2 low and TET2 high groups. Results A total of 136 childhood ALL patients demonstrated lower TET2 expression than control group (P = .038). TET2 mRNA expression levels were correlated with the disease status. In addition, patients with low TET2 expression had lower platelet counts and lower CR rates. Survival analysis showed that low TET2 expression in children with ALL was associated with lower 5-year overall survival (OS) (63% vs 88%, P = .011) and event-free survival (EFS) (60% vs 85%, P = .003). Multivariate analysis revealed that low TET2 expression was an independent poor prognostic factor of OS and EFS. Conclusion Low expression of TET2 in children with ALL is associated with poor prognosis and can be used as a molecular prognostic marker for risk group stratification.

Background In the past decade, miR‐100, miR‐146a, and miR‐210 were reported to be dysregulated in childhood acute lymphoblastic leukemia (ALL). However, effects of genetic variants in these three microRNAs have not been investigated in Chinese population. Methods In this study, we conducted a case‐control study to evaluate the relationship between genetic variants in miR‐100, miR‐146a, and miR‐210 and the risk of childhood ALL in Chinese population. Subsequently, plasma expression level of miR‐100 was also detected. Result We found that subjects carrying mutant homozygous TT genotype of miR‐100 rs543412 had a statistically significantly decreased risk of childhood ALL (adjusted odds ratio [OR] = 0.73, 95% confidence interval [CI] = 0.55‐0.97, P = 0.029). This protective effect was also observed among subjects whose parents were ever drinkers (adjusted OR = 0.53, 95% CI = 0.29‐0.94), or whose living house were ever painted (adjusted OR = 0.57, 95% CI = 0.34‐0.94). Besides, rs543412 variant homozygous TT had a significantly protective role in patients with childhood B‐ALL. Finally, we found that expression level of miR‐100 in plasma of childhood ALL cases was significantly higher than that of noncancer controls. Conclusion Our study suggested that there was significant association between the polymorphisms in miR‐100 (rs543412) and decreased susceptibility to childhood ALL.

Childhood acute lymphoblastic leukemia is one of the most frequent cancers of that age range. Tremendous progress has been achieved in the treatment of these diseases, and increasing numbers of patients are actually cured and live normal lives thereafter. The treatment however remains a complex and serious ordeal. Although statistics are more than encouraging, the specific care of any given patient must be considered with a personalized approach. Among modern tools of disease monitoring, minimal residual disease assessment has earned increasing appeal and now tends to be rather dubbed "measurable" residual disease as the major goal of therapy was the complete eradication of the pathological clone. In this review, the basic characteristics of ALL diagnosis will be briefly recalled, before summarizing available techniques and providing some considerations on the clinical relevance and strategies of childhood ALL MRD evaluation.

BACKGROUND Monitoring minimal residual disease (MRD) in B-lineage acute lymphoblastic leukemia (ALL) to assess treatment response is crucial for risk assignment. Flow cytometry can be used to monitor MRD in ALL but the implementation of this approach requires extensive expertise. If resources are limited, the costs of full flow cytometric MRD testing might be prohibitive. OBJECTIVE We evaluated the applicability of a previously reported simplified MRD assay, designed to distinguish leukemic from normal lymphoblastic during remission induction therapy. METHODS Fifty-nine samples from children with ALL, enrolled in the RE-LLA study at a pediatric oncology center in Recife (Brazil), were evaluated for MRD on day 19 and on day 26 of remission induction therapy. We compared results obtained by a trainee in Recife and an expert. RESULTS The method was implemented successfully and the concordance between results obtained by the trainee and the expert was practically absolute at the end of the study. CONCLUSIONS It is possible to implement reliable measurements of MRD during remission induction therapy in childhood ALL despite limited resources. The simplicity of the MRD method used in this study does not require extensive prior training in leukemia immunophenotyping. © 2016 International Clinical Cytometry Society.

Background/objectives Childhood cranial radiation has irreversible neurocognitive effects. Hyperfractionated radiation therapy (HFX) for acute lymphoblastic leukemia (ALL) was randomized against conventionally fractionated radiation therapy (CFX) in the DFCI 87-01/91-01 trials attempting to minimize these effects. When neurocognitive testing 8-year posttreatment demonstrated no difference, this strategy was abandoned. The objective of this study was to evaluate late social outcomes among patients who received HFX compared to CFX as part of the DFCI 87-01/91-01 trials. Methods This retrospective chart review examined all patients treated according to the DFCI 87-01/91-01 trials at the McMaster Children's Hospital in Hamilton, Canada. Patients

Mercaptopurine (6-mercaptopurine, 6MP) is a mainstay of curative therapy in childhood acute lymphoblastic leukemia (ALL), and contributes to its 90% overall survival rate. We present two patients with ALL who suffered with severe pancreatitis secondary to 6MP. Through the use of allopurinol in conjunction with reduced dose 6MP, we were able to continue 6MP without further pancreatitis. This report contributes to the small body of literature on 6MP associated pancreatitis in childhood ALL and describes a novel approach to continued use of 6MP during therapy.

Background Erwinia asparaginase is antigenically distinct from E.coli‐derived asparaginase and may be used after E.coli‐derived asparaginase hypersensitivity. In a single‐arm, multicenter study, we evaluated nadir serum asparaginase activity (NSAA) and toxicity with intravenously administered asparaginase Erwinia chrysanthemi (IV‐Erwinia) in children and adolescents with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma with hypersensitivity to E.coli‐derived asparaginase. Patients and Methods Between 2012 and 2013, 30 patients (age 1–17 years) enrolled from 10 centers. Patients received IV‐Erwinia, 25,000 IU/m2/dose on Monday/Wednesday/Friday, for 2 consecutive‐weeks (6 doses = 1 cycle) for each dose of pegaspargase remaining in the original treatment plan. The primary objective was to determine the proportion of patients achieving NSAA ≥0.1 IU/ml 48 hr after dose 5 in Cycle 1. Secondary objectives included determining the proportion achieving NSAA ≥0.1 IU/ml 72 hr after Cycle 1 dose 6, and the frequency of asparaginase‐related toxicities. Results Twenty‐six patients completed Cycle 1; 24 were evaluable for NSAA assessment. In Cycle 1, NSAA ≥0.10 IU/ml was detected in 83% of patients (95% confidence interval [CI], 63–95%) 48 hr post‐dose 5 (mean ± SD; 0.32 IU/ml ± 0.23), and in 43% (95% CI, 22–66%) 72 hr post‐dose 6 (mean ± SD; 0.089 IU/ml ± 0.072). For all 30 patients over all cycles, hypersensitivity/infusional reactions with IV‐Erwinia occurred in 37%, pancreatitis 7%, and thrombosis 3%. Conclusions IV‐Erwinia administration in children/adolescents appeared feasible and tolerable. A therapeutically‐effective NSAA (≥0.10 IU/ml) was achieved in most patients at 48 hr, but in fewer than half 72 hr post‐dosing, suggesting that monitoring NSAA levels and/or every 48 hr dosing may be indicated. Pediatr Blood Cancer 2015. © 2015 Wiley Periodicals, Inc.

Acute lymphoblastic leukemia (ALL), the most common malignancy of childhood, is a genetically complex entity that remains a major cause of childhood cancer-related mortality. Major advances in genomic and epigenomic profiling during the past decade have appreciably enhanced knowledge of the biology of de novo and relapsed ALL and have facilitated more precise risk stratification of patients. These achievements have also provided critical insights regarding potentially targetable lesions for the development of new therapeutic approaches in the era of precision medicine. In this review, the authors delineate the current genetic landscape of childhood ALL, emphasizing patient outcomes with contemporary treatment regimens as well as therapeutic implications of newly identified genomic alterations in specific subsets of ALL. Cancer 2015;121:3577–3590. © 2015 American Cancer Society.

Objectives To study E2F3a expression and its clinical significance in children with acute lymphoblastic leukemia (ALL). Methods We quantified E2F3a expression at diagnosis in 148 children with ALL by real-time PCR. In the test cohort (n = 48), receiver operating characteristic (ROC) curve was used to find the best cut-off point to divide the patients into E2F3a low- and high-expression groups. The prognostic significance of E2F3a expression was investigated in the test cohort and confirmed in the validation cohort (n = 100). The correlations of E2F3a expression with the clinical features and treatment outcome of these patients were analyzed. Results ROC curve analysis indicated that the best cut-off point of E2F3a expression was 0.3780. In the test cohort, leukemia-free survival (LFS) and event-free survival (EFS) of the low-expression group were lower than those of the high-expression group (log rank: P = 0.026 for both). This finding was verified in the validation cohort. LFS, EFS, and overall survival were also lower in the low-expression group than in the high-expression group (log rank, P = 0.015, 0.008, and 0.002 respectively). E2F3a low expression was correlated with the existence of BCR-ABL fusion. An algorithm composed of E2F3a expression and minimal residual disease (MRD) could predict relapse or induction failure more precisely than current risk stratification. These results were still significant in the ALL patients without BCR-ABL fusion. Conclusions Low expression of E2F3a was associated with inferior prognosis in childhood ALL. An algorithm composed of E2F3a expression and MRD could predict relapse or induction failure more precisely than that of the current risk stratification.

We evaluated the efficacy of CRT and IT chemotherapy, in addition to conditioning including TBI, for the prevention of CNS relapse, in allogeneic HSCT for childhood ALL. From January 1999 to December 2009, a total of 48 patients, without previous or presenting CNS involvement, underwent HSCT for ALL. All patients received myeloablative conditioning including TBI of 12 or 13.2 Gy and IT chemotherapy twice between days -10 and -2 prior to HSCT. Twenty-five patients received CRT prior to TBI (CRT+), and 23 patients did not (CRT-). CRT+ and CRT- patients had a seven-yr EFS rate of 40.0 ± 9.8% and 41.7 ± 10.6%, respectively (p = 0.8252). The seven-yr relapse rates for CRT+ and CRT- patients were 45.0 ± 11.2% and 38.4 ± 11.6%, respectively (p = 0.7460). CNS relapses were evident in 1 (4.0%) CRT+ patient and 1 (4.4%) CRT- patient (p = 1.000). There were no significant differences in EFS and the probability of CNS relapse between CRT+ and CRT- patients. These results demonstrate that CRT and IT chemotherapy, in addition to conditioning chemotherapy, may not be necessary in childhood ALL patients without previous or presenting CNS involvement.

Background Little is known about childhood ALL in the Middle East. This study was undertaken by MECCA as initial efforts in collaborative data collection to provide clinical and demographic information on children with ALL in the Middle East. Procedure Clinical and laboratory data for patients with ALL between January 2008 and April 2012 were prospectively collected from institutions in 14 Middle East countries and entered into a custom-built-database during induction phase. All laboratory studies including cytogenetics were done at local institutions. Results The 1,171 voluntarily enrolled patients had a mean age of 6.1 ± 3.9 years and 59.2% were boys. T-ALL represented 14.8% and 84.2% had B-precursor ALL. At diagnosis, 5.6% had CNS disease. The distribution of common genetic abnormalities reflected a similar percentage of hyperdiploidy (25.6%), but a lower percentage of ETV6–RUNX1 translocation (14.7%) compared to large series reported from Western populations. By clinical criteria, 47.1% were low/standard risk, 16.9% were intermediate risk, and 36% were high risk. Most patients received all their care at the same unit (96.9%). Patients had excellent induction response to chemotherapy with an overall complete remission rate of 96%. Induction toxicities were acceptable. Conclusions This first collaborative study has established a process for prospective data collection and future multinational collaborative research in the Middle East. Despite the limitations of an incomplete population-based study, it provides the first comprehensive baseline data on clinical characteristics, laboratory evaluation, induction outcome, and toxicity. Further work is planned to uncover possible biologic differences of ALL in the region and to improve diagnosis and management. Pediatr Blood Cancer 2014; 61:1403–1410. © 2014 Wiley Periodicals, Inc.

We report long-term, including final height, auxological data from our retrospective study of non-irradiated survivors of childhood acute lymphoblastic leukaemia (ALL). Body mass index (BMI) standard deviation score (SDS) increases in females, due to increased weight-SDS, persisted to final height, with probable adverse long-term health outcomes. In contrast, males demonstrated increased BMI-SDS in follow-up, due to reduced height-SDS, not increased weight-SDS, but such changes had resolved by final height. Childhood ALL survivors, particularly females, are therefore at potential increased risk of developing the metabolic syndrome during follow-up. We recommend that strategies to minimize weight gain should be implemented during ALL treatment.

Background Treatment of childhood acute lymphoblastic leukemia (ALL) has been available in Saudi Arabia (SA) for over 30 years; however, only limited data have been published from there. This study was conducted to establish processes for collaborative data collection and provide clinical characteristics and outcome of children with ALL in SA. Procedure Clinical data for patients diagnosed from 2004 to 2008 were retrospectively collected at eight institutions and entered remotely into a custom-built database. Statistics regarding clinical and genetic characteristics and treatment outcome were calculated. Results The 594 evaluable patients had a median age of 4.37 years and 56.4% were boys. Majority of patients had B-precursor ALL while 10.7% had T-ALL. CNS leukemia was present in 5.2% of patients. The distribution of common genetic abnormalities was similar to that reported from western populations, with 24.6% hyperdiploidy, 21% RUNX1-ETV6 positivity, 4.2% BCR-ABL1 positivity, and 2.5% with MLL gene rearrangement. Patients received risk-adapted therapy according to various protocols, although treatment strategies for the majority were similar. Five-year OS, RFS and EFS were 86.9%, 79.1%, and 73.3%, respectively. The OS for patients with pre-B ALL was significantly higher than for T-ALL (88.0% vs. 71.8%; P = 0.019, Log-Rank test). Patients with pre-B ALL categorized as low-risk by NCI/Rome criteria and those with hyperdiploidy had OS of 93.4% and 95.8%, respectively. Conclusions The characteristics of childhood ALL in SA are similar to those observed in developed countries. Future prospective studies utilizing unified national protocols are needed to further improve the outcome of our patients. Pediatr Blood Cancer 2014;61:74–80. © 2013 Wiley Periodicals, Inc.

Background Osteonecrosis (ON) is a severe complication of acute lymphoblastic leukemia (ALL) treatments. Recent studies suggest that bisphosphonates might reduce pain and loss of motor function in patients with ON. We assessed the effects of pamidronate compared to standard care in patients with symptomatic ON (sON) and studied whether steroids might be continued after diagnosis of ON in some patients. Methods We evaluated 17 patients with sON as complication of primary ALL treatment between 2000 and 2008. Fourteen patients were treated with pamidronate. Mobility and pain control were monitored in all patients. Affected joints were classified by magnetic resonance imaging (MRI) at ON diagnosis and after 6–72 months. Results Out of 220 patients with ALL, 17 (7.7%) patients developed sON. The median age at ALL diagnosis was 11 years (range: 2.7–16.6 years) and sON occurred a median of 13.4 months (range: 2.5–34 months) after ALL diagnosis. Affected joints were hip, knee and ankle. MRI scans showed 7 severe, 4 moderate, and 6 mild ON lesions. Fourteen patients showed improvement in pain (77% of patients) and motor function (59% of patients), even though corticoids were reintroduced in 4 patients. MRI demonstrated improvement, stability or worsening in 6, 3, and 5 cases, respectively. Conclusions Pamidronate seems to be effective in the management of pain and motor function recovery in sON. Further studies are needed to provide evidence as to whether bisphosphonates can be recommended for the treatment or the prevention of ON in childhood ALL patients. Pediatr Blood Cancer 2013; 60: 741–747. © 2012 Wiley Periodicals, Inc.

Background It has been proposed that infections in infancy and early childhood are associated with a reduced risk of childhood acute lymphoblastic leukaemia (ALL). We tested this hypothesis in a register-based study of hospitalisations for infectious diseases prior to diagnosis of childhood ALL. Procedure A nation-wide cohort encompassing all Danish children aged 0–14 years and born between 1977 and 2008 (N = 1,778,129) was established and followed for hospitalisations for infectious diseases and risk of childhood ALL. The exposure was lagged 1 year to limit reverse causality. In the statistical analyses exposure was defined as (time dependent) number of early or late (before 2 or at/after 2 years of age) hospitalisations to further explore possible age-dependent associations. Results A total of 815 children were diagnosed with ALL during follow-up. Risk of ALL was associated neither with hospitalisations for infectious diseases before (incidence rate ratio = 0.92, 95% confidence interval 0.78–1.07) nor at/after 2 years of age (incidence rate ratio = 1.04, 95% confidence interval 0.81–1.32). This also applied to subsets of ALL supposedly initiated prenatally. Conclusion The absence of association between hospitalisation for infections and risk of childhood ALL directs future investigations of the role of infections in development of childhood ALL towards exploration of less severe infections. Pediatr Blood Cancer 2013; 60: 428–432. © 2012 Wiley Periodicals, Inc.

BACKGROUND: With the improved survival of childhood acute lymphoblastic leukemia (ALL), the effect of treatment on psychosocial well-being becomes increasingly relevant. Literature on sleep and fatigue during treatment is emerging. However, information on these subjects after treatment is sparse. This cross-sectional study examined sleep and fatigue in relation to depression and quality of life (QoL) after treatment for childhood ALL. PROCEDURE: Sleep, fatigue, depression, and QoL were evaluated by parent proxy and/or child self-reports of the Children's Sleep Habits Questionnaire, the PedsQL multidimensional fatigue scale, the Children's Depression Inventory and the Child Health Questionnaire. All total scores were compared to Dutch norm references. RESULTS: Sixty-two children were included, being 36 (interquartile range 22-62) months after finishing treatment. Parents rated the ALL survivors as having more disturbed sleep, more fatigue and poorer physical QoL compared to the Dutch norm. ALL survivors themselves reported less sleep problems, less depressive symptoms, and better psychosocial QoL than the Dutch norm. More sleep disturbances and fatigue correlated with more symptoms of depression and a worse QoL. CONCLUSIONS: Differences in parental and self-reports, including worse parental ratings, might be explained by worried parents and/or the adaptive style of the children. Impaired sleep and fatigue correlated with more depressive symptoms and a worse QoL.

Acute lymphoblastic leukemia (ALL) is the most common type of pediatric neoplasia. Highly heterogeneous, ALL includes several genetic subtypes with varying clinical outcome. Although, some features are well established as prognostic predictors, the details of the molecular mechanisms underlying different phenotypes are only beginning to emerge. Recently, microRNAs (miRNAs) have been shown to influence a range of physiological processes and, consequently, alterations in their expression and functions have been associated with the development of many cancers, including leukemia. This article aims to review the current state of knowledge of the role of miRNAs on the biology of childhood ALL, also including relevant findings from the adult leukemia literature.

It is plausible that exposure of the parents before birth or of the child to sources of benzene increases the risk of childhood acute lymphoblastic leukaemia (ALL). The aim of this analysis was to investigate whether refuelling a vehicle with petrol before birth or burning wood to heat the home before or after the child's birth increased the risk of childhood ALL. Data from 389 cases and 876 frequency-matched controls were analysed using unconditional logistic regression, adjusting for study matching factors and potential confounders. The odds ratio (OR) for the mother ever refuelling a vehicle with petrol for non-occupational purposes before or during the pregnancy was 0.97 [95% confidence interval (CI) 0.69, 1.38]. The OR for the father for this exposure in the year before conception was 0.88 [95% CI 0.52, 1.48]. The OR for use of a closed wood burner to heat the home in the year before or during pregnancy was 1.41 [95% CI 1.02, 1.94] and 1.25 [95% CI 0.92, 1.70] after birth. We found no evidence that non-occupational refuelling a vehicle with petrol in the year before or during pregnancy increased the risk of ALL in the offspring. There was weak evidence that burning wood in a closed burner to heat the home increased the risk, but there was no dose-response relationship and chance could explain the finding.

Background Neurocognitive impairment occurs in 20%-40% of childhood acute lymphoblastic leukemia (ALL) survivors, possibly mediated by folate depletion and homocysteine elevation following methotrexate treatment. We evaluated the relationship between folate pathway polymorphisms and neurocognitive impairment after childhood ALL chemotherapy.

Background Accurate data about childhood acute lymphoblastic leukemia (ALL) in low- and middle-income countries are lacking. Our study is designed to assess survival of childhood ALL at King Hussein Cancer Center (KHCC) using modified St. Jude Children's Research Hospital protocols. Patients and methods We reviewed the medical records of children 1–18 years of age who were diagnosed with ALL and treated at KHCC from January 2003 through December 2009. Disease characteristics and outcome were analyzed. Results Over a 7-year period, 300 children with ALL were treated. One hundred and seventy-three (57.7%) were males and 127 (42.3%) were females. The median age at diagnosis was 5 years. One hundred and fifty-seven (52.3%) children were classified as low-risk, 118 (39.3%) were standard-risk and 25 (8.3%) were high-risk. Two hundred and sixty-two (88.5%) children had pre-B cell phenotype and 34 (11.5%) had T-cell phenotype. Two hundred and seventy-three (91.3%) children were classified as having CNS I disease, 24 (8%) had CNS II, and 2 (0.67%) had CNS III. Cytogenetic abnormalities included: t(12;21) in 30 (12%) children and t(9;22) in 18 (7.4%). Four (1.3%) children died in induction, 6 (2%) died in first remission and 27 (9%) relapsed. After a median follow-up of 34.5 months (range 0.32–84.5), the estimated 5-year event free survival and overall survival were 80% and 89%, respectively. Conclusion Treatment protocols developed by major cooperative groups and institutions to treat childhood ALL was successfully adapted and suggest that such an approach may be useful in other low- and middle-income countries. Pediatr Blood Cancer 2011; 57: 385–391. © 2011 Wiley-Liss, Inc.

Background Survivors of childhood acute lymphoblastic leukemia (ALL) are vulnerable to exaggeration of the aging process including decreased bone mineral density (BMD). As little is known about their dietary or nutrient intake that may affect their long-term bone health, we examined nutrient intake in long-term survivors of childhood ALL.

Karyotyping along with a 3-probe fluorescent in situ hybridisation (FISH) strategy was used to risk stratify therapy in 303 children with B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). Of the 166 patients risk stratified, karyotype identified 91 (55%). FISH identified all karyotypes accurately, with the exception of hypodiploidy, and risk-stratified an additional 75 patients. The frequency of ETV6-RUNX1 is lower and high hyperdiploidy, higher than reported in the west. An adapted 3-probe FISH strategy identified two patients with ETV6-ABL1 fusion who received Imatinib. In limited-resource settings, a 3-probe FISH approach provides a practical approach for risk-stratified therapy in childhood ALL.

The remarkable progress in the treatment of childhood acute lymphoblastic leukaemia (ALL) has been based on the adjustment of therapy to subgroups of leukaemia stratified by their prognostic implications. Here, the contribution of the last decade of advanced genomic research on the clinical management of childhood ALL is examined. The application of genomics for routine diagnosis of ALL is feasible but depends on commercial development of appropriate certified platforms. The discovery of several novel high-risk markers, such as deletions in IKZF1 might be integrated into clinical protocols in the near future. Several novel targets for therapy have been identified and have led to phase I/II therapeutic trials. This and any future progress depends on the maintenance of high quality bio-banks including biological material and clinical data of each patient enrolled on a prospective clinical protocol.

Aim: To objectively measure levels of physical activity in children, following treatment for acute lymphoblastic leukaemia (ALL). Methods: Nineteen children who had completed treatment for ALL 6 months–5 years prior to study enrolment wore an accelerometer for 2 weekdays and 2 weekend days. Results: The children spent an average of 141 ± 74 min/day engaged in moderate to vigorous physical activity (MVPA), an amount similar to that previously documented in healthy children. Only three of the 19 subjects averaged less MVPA than the recommended amount (at least 60 min/day). MVPA levels were significantly higher on weekdays than weekend days (P= 0.006). Overall, boys engaged in significantly more MVPA than girls (P= 0.029). MVPA time was negatively correlated with age (r =−0.80) and age at diagnosis (r =−0.87). No trend between MVPA and time off treatment or body mass index was identified. Conclusions: Survivors of childhood ALL appear to be engaging in similar amounts of MVPA as those of the healthy children and are meeting recommended levels of physical activity.

Background Osteonecrosis is a well-recognised complication of current childhood acute lymphoblastic leukaemia (ALL) therapy. There are few studies on the medical management of osteonecrosis in this setting. We studied the therapeutic and radiological effects of oral and intravenous bisphosphonate use compared with standard care as treatment for osteonecrosis in this population. Method Patients who developed osteonecrosis as a complication of ALL therapy between 1994 and 2007 were treated at a single paediatric institution. Of 17 patients, 9 were commenced on bisphosphonates and 8 treated conservatively. Both groups were observed with time. Pain, analgesic requirement and musculoskeletal function were assessed monthly. Affected joints were radiologically imaged at set intervals. Each scan was graded using an ellipsoid method to give the total volume of osteonecrosis, by blinded radiologic examination. Results Three of six patients treated with oral alendronate showed clinical improvement. The three patients that had no improvement were subsequently treated with intravenous pamidronate. All six patients treated with intravenous pamidronate showed clinical improvement. Seven of eight conservatively treated patients deteriorated clinically. All patients demonstrated reduction in the radiological burden of osteonecrosis with time. There was no difference in the rate of reduction between conservative and bisphosphonate arms. Conclusion Bisphosphonate use, in particular pamidronate, improved pain scores, analgesic requirement and musculoskeletal function in patients with osteonecrosis occurring as a complication of childhood ALL therapy. Objective radiologic benefit of bisphosphonate treatment could not be demonstrated. Risks, benefits and long-term outcome of bisphosphonate use in this population should be addressed in a larger prospective, randomised trial. Pediatr Blood Cancer 2010;54:934–940 © 2010 Wiley-Liss, Inc.

Background Acute lymphoblastic leukemia (ALL) is the most common and curable malignant pediatric disease in children. In low- and middle-income countries, however, economic factors prevent many patients from receiving complete treatment, even as government and insurance entities lack complete data on the costs for ALL therapies. Here, we analyzed the overall costs for pediatric ALL therapies and their constitutive elements. Procedure All cost information was drawn from our hospital database. We analyzed the costs of 45 newly diagnosed children with ALL from May 2005 to June 2006; 20 were classified into low-risk group, 25 into medium-risk group, and all had completed the ALL-2005 protocol treatment. Forty cases were B-lineage, four were T-lineage, and one was double-lymphoid lineage. Results Average total clinic expense per person was US $3,694.58 ± 1,376.85. Average total in-hospital expense per patient was US $7,299.48 ± 6,526.39, with a large individual difference. Medicine and laboratory test costs represented 40.5% and 21.5%, respectively. Patients stayed at home or attended clinic for more than 90% of the therapy period. In-hospital and clinic constituted 66.4% and 33.6% of costs, respectively. Costs among risk groups and with/without severe complications differed significantly (P

Background Survival of children with ALL, in developing nations has not kept pace with cure rates in developed countries. Our study was designed to assess survival data and identify risk factors. Procedure Data of 762 patients with ALL were analyzed. Information regarding the clinical-demographic profile, therapy and course of illness were recorded. Status and duration at last follow-up were utilized to generate Kaplan–Meier survival curves. Results The mean age was 5.7 ± 0.23 years (M/F, 3.2:1). Parents of 230 (30.2%) patients opted for no therapy. There were 68 and 60 deaths in induction and remission phases respectively. Besides these, 111 children either defaulted therapy or were lost to follow up. Relapsed disease was documented in 125 cases. The 5-year OS and EFS was 46% and 43% respectively. Survival analysis, using the Cox multivariate regression, for gender (P = 0.659, CI: 0.852–1.161), age (P = 0.943, CI: 0.725–1.225), symptom-diagnosis interval (P = 0.002, CI: 1.116–1.668), WCC (P

The ability of monocyte differentiation in childhood acute lymphoblastic leukaemia (ALL) was evaluated on the basis of the ultrastructure and peroxidase (PO) activity which could show the differentiation of cultured monocytes. In the control, PO activity limited to the granules decreased time-dependently during culture for 4 d, and was closely associated with the morphological development to macrophages. In childhood ALL, monocytes showed poor changes in both PO activity and morphological features during culture for 4 d compared to the control. Therefore, we conclude that monocyte to macrophage differentiation is impaired in childhood ALL.

Purpose To look for the presence and age-dependence of late structural alterations of otherwise normal-appearing cerebral gray and white matter after radiation and chemotherapy in adult survivors of acute lymphoblastic leukemia (ALL) during childhood. Materials and Methods In a group of 13 adult survivors 17–37 years old, who had been treated by total brain radiation (18–24 Gy) and chemotherapy 16–28 years ago, prospective MR examinations including diffusion tensor imaging (DTI) were performed. Evaluation included volumetry, calculation of mean diffusivity (MD) and fractional anisotropy (FA), and comparison of results to an age-matched control group. Results DTI showed significantly reduced FA values in the temporal lobes (difference of 0.069 units, P < 0.001), hippocampi (difference of 0.033 units, P < 0.001), and thalami (difference of 0.046 units, P = 0.001), which were accompanied by significant white matter volume loss (difference of 92 cm3, P < 0.001). Significant elevations of MD were limited to the temporal white matter (difference of 42 × 10−6 mm2/s, P = 0.005). Global and frontal white matter MD correlated negatively to increasing age of the survivors (P < 0.01). Conclusion With regard to structural white matter alterations, adult long-term survivors of childhood ALL, who had received total brain radiation and chemotherapy, apparently show the same overall age dependence as controls. Follow-up studies are needed for confirmation. J. Magn. Reson. Imaging 2008;27:1250–1255. © 2008 Wiley-Liss, Inc.

Aims Evaluation of l-asparaginase therapy in the NOPHO-92 ALL-protocol (treatment protocol of acute lymphoblastic leukaemia of the Nordic Society of Paediatric Haematology and Oncology, initiated in 1992) after intravenous and intramuscular administration of Erwinia asparaginase during induction and re-induction therapy. Methods Forty children with newly diagnosed acute lymphoblastic leukaemia received Erwinia asparaginase (30 000 IU/m2 i.v. or i.m.) during induction therapy (every day for 10 days), and 19 children received Erwinia asparaginase (30 000 IU/m2 i.v. or i.m.) during re-induction therapy (twice a week for 2 weeks). Within the treatment periods asparaginase trough activity (using a spectrophotometric assay) was determined on specific days. The goal of therapy is complete l-asparagine depletion, which asparaginase activities above 100 IU l−1 have been shown to ensure. Therefore determination of l-asparagine (using a h.p.l.c. method) was performed only in plasma samples with asparaginase activities below 100 IU l−1. Results During induction therapy 92.2% of the trough enzyme activities were above 500 IU l−1 for the i.v.-treated patients, and 92.4% of the trough enzyme activities were above 500 IU l−1 for the i.m.-treated patients. During re-induction therapy 64.7% of the trough enzyme activities were below 100 IU l−1 in the i.v.-treated group, and 73.3% of the trough enzyme activities were below 100 IU l−1 in the i.m.-treated group. For trough enzyme activities below 100 IU l−1l-asparagine depletion was complete in two thirds of the samples. Conclusions In the NOPHO-92 ALL-protocol l-asparaginase treatment during induction therapy was unnecessarily intense, but during the re-induction phase it appeared inadequate.

Paediatric acute lymphoblastic leukaemia (ALL) has provided a landmark in cancer therapy as the first disseminated and otherwise lethal malignancy to be curable in the majority of patients. Although the success rate is high, this benefit is achieved through a long, invasive and very arduous treatment process. The experience of undergoing such intensive treatments affects not only the child, but the entire family. To date, however, psychosocial research is only beginning to describe the depth and breadth of the impact on families of this experience. This paper presents findings from a recent qualitative study of families coping with the initial stage (induction remission) of treatment for childhood ALL. The findings indicate that the experience is so profoundly disturbing and disruptive that it challenges the families' sense of normalcy and stability. These findings provide evidence of significant hardship and stress, with the consequent indication of the need for social work support. Above all, such families need to hear the comforting message from social workers that what they are experiencing is normal under the circumstances. Along with practical assistance, they need reassurance about the intensity of feelings they will experience and an affirmation of the difficulty of the challenges they face.

BACKGROUND: WBC reduction offers a variety of benefits to patients requiring multiple transfusions during induction therapy for childhood acute lymphoid leukemia (ALL), including reductions in febrile transfusion reactions, HLA alloimmunization, and CMV transmission. One potential benefit is a reduction in the deleterious effects of transfusion immunomodulation. In the surgical setting, transfusion immunomodulation has been linked to increases in postoperative infections and decreases in host cellular immunity that are mitigated by WBC reduction of transfused blood. STUDY DESIGN AND METHODS: A retrospective review was conducted of the medical records of 68 consecutive children undergoing induction therapy for newly diagnosed ALL from 1988 through 1995, a period whose midpoint is 1991, the year WBC reduction was introduced in this hospital. RESULTS: WBC reduction of platelet and RBC transfusions was associated with fewer days with fever (mean, 5.7 days [no WBC reduction] and 2.1 days [WBC reduction]; p = 0.012) and days with positive microbial cultures (mean, 1.5 [no WBC reduction] and 0.71 [WBC reduction]; p = 0.0055). There were more high-risk ALL patients in the group receiving WBC-reduced transfusions. CONCLUSION: Allogeneic WBCs in transfused blood may cause impairment of host defenses against microbial infection during induction therapy for childhood ALL.

Summary. We studied the expression of HoxA9 and Meis1 by reverse transcriptase-polymerase chain reaction analysis in leukaemic cells from cases of infant acute lymphoblastic leukaemia (ALL, n = 27) and childhood ALL (n = 29). These two genes were co-expressed significantly more frequently in infant ALL than in childhood ALL (19/27 vs0/29 cases, P

Over the last 10 years genetic variation in folate metabolism has received considerable scientific attention, but findings have been inconsistent, with many studies based on small numbers. Koppen et al (2010) recently reported on a meta-analysis of 14 studies that had investigated genetic polymorphisms in enzymes involved in folate metabolism in relation to both childhood and adult acute lymphoblastic leukaemia (ALL), concluding that both MTHFR 677 C>T and MTHFR 1298A>C were likely to be associated with decreased susceptibility to ALL in childhood. We were however, somewhat surprised to see the authors combined data from children and adults in the same plot, despite the fact that two previous meta-analyses, neither of which were referenced by Koppen et al (2010), stratified their data by diagnostic age (Pereira et al, 2006; Zintzaras et al, 2006). Indeed, the meta-analysis plots of childhood ALL (Figures 1 and ​and22 reproduced from Koppen et al, 2010) included two studies that contained no data on children at all (Skibola et al, 1999; Gemmati et al, 2004) as well as one study that comprised both children and adults (Chiusolo et al, 2004). Whilst this was acknowledged in the text in the case of the study by Gemmati et al (2004), no such recognition was afforded our ownUKstudy (Skibola et al, 1999). Moreover several published studies where no association with MTHFR 677 was observed are missing from the review, including data from Canada (Krajinovic et al, 2004)(n = 270), Turkey (Balta et al, 2003) (n = 144) and Slovenia (Petra et al, 2007) (n = 68). Fig. 1 MTHFR 677CT and susceptibility to childhood ALL reproduced from Koppen et al, 2010. Fig. 2 MTHFR 1298AC and susceptibility to childhood ALL, reproduced from Koppen et al, 2010. From their comprehensive meta analysis of 4894 individuals Pereira et al (2006) concluded that whilst the MTHFR 677 polymorphism is important for risk of ALL, it is confined to adults. This is supported by recent data from the largest study to date, which included 939 children with ALL recruited into the United Kingdom Childhood Cancer Study (http://www.UKCCS.org) (Lightfoot et al, 2010). Given the missing childhood data and the inclusion of adult data, we believe that the conclusion for a protective role for MTHFR among children drawn by the authors of the recent meta-analysis (Koppen et al, 2010), is misleading.

Late relapse after successful treatment of acute lymphoblastic leukaemia (ALL) in children is well-recognized but rare. It is often uncertain whether this represents a true relapse of the original disease or a second malignancy. We present the case of a patient who relapsed 14 years after the original diagnosis of childhood ALL in whom both the original leukaemic cells and those taken at relapse had an identical T cell receptor gamma (TCRG) gene rearrangement. This analysis confirms that this relapse is a true re-emergence of the patient's original disease. The term 'cure' should be used with caution in childhood ALL, even after long periods in continuous remission.