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Total body irradiation (TBI)/cyclophosphamide (CY) is a standard-of-care conditioning regimen in allogeneic hematopoietic stem cell transplant (HSCT) for pediatric acute lymphoblastic leukemia (ALL). This study sought to identify whether the addition of thiotepa (TT) to TBI/CY improves HSCT outcomes for pediatric patients with ALL. A retrospective analysis was performed on 347 pediatric ALL patients who underwent HSCT between 1995 and 2015, with 242 receiving TBI/CY/TT and 105 patients receiving TBI/CY. There were no statistical differences in age, donor source, or complete remission status between the 2 groups. Comparison of the TBI/CY/TT versus TBI/CY groups demonstrated no difference in transplant-related mortality at 1 (11% versus 11%), 5 (13% versus 16%), or 10 years (16% versus 16%). There was lower relapse in the TBI/CY/TT group at 1 (14% versus 26%), 5 (24% versus 36%), 10 (26% versus 37%), and 15 years (26% versus 37%) (P= .02) but was not statistically significant on multivariate analysis. The TBI/CY/TT group showed a trend toward improved disease-free survival (DFS) at 5 (59% versus 47%), 10 (56% versus 46%), and 15 years (49% versus 40%) (P = .05) but was not statistically significant on multivariate analysis. Comparing overall survival at 5 (62% versus 53%), 10 (57% versus 50%), and 15 years (50% versus 44%) demonstrated no statistical difference between the 2 groups. The addition of thiotepa to TBI/CY demonstrated no increase in transplant-related mortality for pediatric ALL HSCT but was unable to demonstrate significant benefit in disease control. Minimal residual disease status remained the key risk factor impacting both relapse and DFS. More studies are warranted to better clarify the benefits of using thiotepa in conditioning for ALL HSCT.

Precision medicine seeks to improve health care by individualizing treatment based on a person’s genetic predispositions, lifestyle, and environment. While this approach holds great promise for improving health care, its potential relevance to population health disparities is not clear. Pediatric acute lymphoblastic leukemia provides an example to illustrate the complexity of the issue. African American (AA) children have a lower incidence of acute lymphoblastic leukemia (ALL), due in part to a lower prevalence of gene variants associated with risk, but experience higher relapse rates than European American (EA) children after treatment. AA children are also more likely to present with poor prognostic indicators at the time of diagnosis. Numerous environmental exposures have been associated with ALL risk, but effect sizes are small and studies are lacking to assess whether differential exposure could account for the observed racial disparities. Gene variants associated with treatment response can partially account for higher relapse rates in AA children. This finding could reflect the optimization of current chemotherapy regimens in predominantly EA populations. Importantly, the higher relapse rate seen for AA children in national data was not observed in a care setting that included elimination of out of pocket costs, risk-directed therapy based on stringent risk stratification, and rigorous case management. The ALL example illustrates the importance of social factors in addressing health disparities, including access to effective treatment and inclusion of diverse populations in research, but also points to important ways in which precision health research can help to illuminate disease processes and contribute to improving effective treatment for all patients.

Objective: To describe a rare presentation of acute lymphoblastic leukemia (ALL) that is important to the field of pediatric otolaryngology. Methods: The case of a nine-year old female who presented with left periorbital edema as her initial symptom of ALL was reviewed along with pertinent literature. Results: At the time of patient's initial presentation, a computed tomography scan of the sinuses showed sphenoid sinus opacification and left lateral rectus muscle enlargement. She was started on antibiotics without improvement. Subsequently, magnetic resonance imaging of the brain demonstrated an infiltrative process involving the sphenoid sinus marrow space, lateral rectus muscles and dura. Her peripheral blood count revealed 40% blasts, and a bone marrow biopsy demonstrated B-cell ALL. She immediately underwent induction chemotherapy, and her post-induction bone marrow biopsy showed no evidence of residual disease. Conclusion: This case highlights the importance of understanding and considering rare, aggressive diseases that can masquerade as simple periorbital edema. Keywords: Acute lymphoblastic leukemia, ALL, Periorbital swelling, Periorbital edema, Proptosis

Context Pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are heterogeneous diseases mediated by changes in protein expression. As most chemotherapeutic agents target proteins, and because overall survival of pediatric AML is far inferior to both pre-B and T-ALL, we aimed to compare the proteomic landscape of pediatric T-ALL and AML. Objective To compare protein expression in pediatric T-ALL and AML. DESIGN: Reverse phase protein arrays (RPPA) analysis was used to measure protein expression in 858 acute leukemia samples (358 T-ALL and 500 AML) and 61 normal CD34+ samples using 270 validated antibodies. Results Of the 270 analyzed proteins, 136 proteins (50%) were differentially expressed between T-ALL and AML; 61 were higher in T-ALL, 75 in AML (P Conclusions This study provides support for our previous hypothesis that pediatric T-ALL and AML can be characterized by recurrent protein expression patterns. While most PC and CON were found in both diseases, SIG were specific to either T-ALL or AML. We found similar results when comparing B-ALL to AML in adults. Shared CON indicate that there are common features between pediatric T-ALL and AML. Proteins or pathways with similar utilization in both diseases may allow for information on clinical utility from one disease to be applicable to the other. Those with differential utilization are likely to be uninformative with respect to clinical utility in the other disease. Grant Funding R01 CA164024 and R01 CA193776

Background CART19-related toxicities may require treatment inpatient or in the ICU. We sought to describe inpatient/ICU resource utilization within 30 days of CART19 infusion and evaluate trends in resource utilization from 2012-2019. Methods We identified patients (pts) with ALL treated with CART19 on a clinical trial (NCT01626495, NCT02906371, and NCT02374333) or with the commercial product, tisagenlecleucel, at Children's Hospital of Philadelphia. Demographic, pharmacy, and inpatient data were extracted from the EHR from day of infusion (d0) to d+30 using a semi-automated EPIC data query tool. The Virtual Pediatric Systems database was queried for resource utilization data and PRISM 3 and PIM 2 severity of illness scores. Log-binomial and linear regression were used to estimate the association of patient characteristics with inpatient/ICU admission and inpatient/ICU length of stay (LOS). Similar models were used to estimate trends over time. Results The analyses included 213 pts. Median age was 12y (range 1-29y); 60% were male. Prior to CART19, 42% had an alloHCT. Pre-infusion, 19% had high tumor burden (HTB), defined as bone marrow blasts ≥40%. From 2012-2019, the proportion of pts with prior alloHCT or HTB decreased (Table 1). CART19 was infused in the outpatient setting in 198 (93%) pts. From d0 to d+30, 149 (70%) had ≥1 inpatient admission, starting at a median of d+2 (IQR +1 to +6). Among admitted pts, median cumulative inpatient LOS was 7d (IQR 4-13). From 2012-2019, there were linear trends toward decreases in proportion of pts admitted (p ICU admission was required for 49 (23%) pts, starting at a median of day +5 (IQR +4 to +7). ICU admission was more frequent for pts with HTB [HTB, 68% (95% CI, 52-81) vs. low burden, 11% (95% CI, 7-17), p Other than HTB, baseline characteristics were not associated with inpatient/ICU admission or LOS. Conclusion In a cohort of 213 pediatric pts, over 90% were safely infused with CART19 in the outpatient setting. Though 70% required at least one admission, the proportion of pts admitted to the hospital or ICU and cumulative inpatient LOS decreased over the past 7 years.

We developed and validated a quantification method for methotrexate (MTX) polyglutamates (MTX-PGs, MTX-PG1 to MTX-PG5) by liquid chromatography-tandem mass spectrometry using stable isotope-labeled internal standards and applied to 196 clinical samples collected from pediatric acute lymphoblastic leukemia patients treated with MTX. MTX-PGs levels and their proportions (%) in sum of all MTX-PGs (MTXSum) were evaluated in relation to TPMT, NUDT15, and MTHFR genotypes. For the developed method, linearity ranges 1-500 nmol/L, bias for accuracy 0.3-13.5 %, coefficient of variation for within- and between-run imprecision of 3.2-9.5% and 1.5-12.0%, respectively. Recoveries achieved were 74.2-105.8 %. There was no significant carryover. The median level of the MTXSum for 196 clinical samples was 129.4 nmol/L (interquartile range 28.1-241.2). MTX dose and MTX-PGs were associated (P < 0.05) and among five MTX-PGs, MTX-PG3 was the predominant form (median 41.7 %). The MTX-PG3 level was significantly higher in patients with TPMT *1/*3C than in patients with wild type and MTX-PG3% was significantly higher and MTX-PG5% was significantly lower in NUDT15 intermediate metabolizers than normal or indeterminate phenotypes (P < 0.05). This validated MTX-PGs quantification method can facilitate a better understanding of MTX metabolism and therapeutic drug monitoring for MTX treatment.

Objectives The treatment of pediatric acute lymphoblastic leukemias (ALL) has seen remarkable advances recently. However, relapse occurs in approximately 20% of cases which necessitates identifying additional high risk parameters for treatment intensification. The aim of this study is to assess the prognostic significance of CD45 antigen expression in pediatric ALL. Methods We studied 363 pediatric patients with B cell precursor-ALL (BCP-ALL) (n = 313) and T-ALL (n = 50). The ratio of median fluorescence intensity of CD45 expressed in leukemic blasts and normal lymphocytes was calculated. The 75th percentile was taken as cut-off to categorise patients into CD45 high and CD45 low groups. Results The 75th percentile was 0.141 in BCP-ALL and 0.548 in T-ALL. In BCP-ALL, there was a statistically significant association of age (≥10 years) (p = 0.027) and National Cancer Institute high risk group (p = 0.001) with high CD45 expression but not in T-ALL. Worse event-free survival (EFS) was seen with high CD45 expression in BCP-ALL (42.17% versus 60.83%, p = 0.0053). In T-ALL, there was no association between CD45 expression and EFS (CD45 high 40.40% versus low 67.35%, p = 0.414). The overall survival (OS) was 70% versus 60% (p = 0.38) in BCP-ALL and the OS was 82% versus 68% (p = 0.16) in T-ALL for CD45 low versus CD45 high groups, respectively. Conclusion We conclude that high CD45 surface expression is associated with worse EFS in pediatric BCP-ALL.

To investigate the prognostic value of PRAME expression in pediatric acute lymphoblastic leukemia(ALL), we measured PRAME transcript levels at diagnosis in 191 patients(146 B-ALL; 45T-ALL)receiving chemotherapy only. PRAME overexpression was defined as transcript levels higher than 0.30%, which is the upper limit of normal bone marrow and the optimal cutoff value derived from ROC curve analysis. PRAME overexpression was identified in 45.5% of patients. In B-ALL, PRAME overexpression was significantly associated with lower CIR(cumulative incidence of relapse), higher DFS (disease-freesurvival), and OS(overall survival) rates at 3 years, respectively (5.8% vs. 14.9%, P = 0.014; 94.2% vs. 85.1%, P = 0.014; 96.0% vs. 87.4%, P = 0.039). PRAME overexpression had no impact on outcome in T-ALL patients. Among B-ALL patients with non-poor cytogenetic risk, those with PRAME overexpression showed significantly lower CIR, higher DFS and OS rates at 3 years, respectively (8.47% vs. 14.5%, P = 0.009; 96.5% vs. 85.5%, P = 0.009; 98.4% vs. 88.0%, P = 0.023). Furthermore, PRAME overexpression was an independent good prognostic factor for relapse in all B-ALL patients and B-ALL patients with non-poor cytogenetic risk. Therefore, the prognostic significance of PRAME overexpression differed by ALL subtype; It predicted good outcome in pediatric B-ALL receiving chemotherapy.

OncomiRs are microRNAs that are associated with early onset of specific cancers. To identify microRNAs involved in pediatric acute lymphoblastic leukemia (ALL) subtypes T-ALL and B-ALL, peripheral blood and bone marrow samples were independently subjected to microarray analysis using two different high-fidelity array platforms. The unique and common gene signatures from both arrays were validated by TaqMan individual assays in 100 pediatric ALL samples. Survival studies were carried out in the test set and validation set with 50 randomly selected samples in each set. MicroRNA expression profile revealed characteristic signatures for distinguishing T and B lineages and identified 51 novel microRNAs in pediatric ALL. Interestingly, the present study also revealed endogenous similarities and differences between blood and bone marrow within each ALL subtype. When Cox regression analysis was carried out with these identified microRNAs, 11 of them exhibited expression levels significantly correlated with survival. Validation of some of the common and relevant microRNAs from both arrays showed that their targets are involved in key oncogenic signaling pathways. Thus, this study suggests that microRNAs have the potential to become important diagnostic tools for identification and monitoring clinical outcomes in ALL patients.

Introduction Access to hematopoietic stem cell transplantation (HSCT) in pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) is heavily dependent on disease-related factors but may be influenced by social and economic determinants. Studies from countries with privatized health care systems suggest reduced access by race and socioeconomic status. Objectives We sought to determine whether access to HSCT is affected by socio-demographic (race and income) and regional-geographic factors within a publically funded health care system in a geographically vast country with broad ethnic diversity using a population based dataset. Methods We included all children Results Of children with ALL, 325 of 3992 (8.1%) received a HSCT, with 41.5% occurring in CR1 and 58.5% in CR2. Of children with AML, 278 of 632 (44%) received HSCT, with 62.2% occurring in CR1 and 37.8% occurring in CR2. In multivariable analysis, factors that were independently associated with increased odds of receiving HSCT in ALL and AML are shown in Table 1. In both groups, no association was found between race or neighborhood income quintile and eventual receipt of HSCT. Conclusion Patients diagnosed at a HSCT performing center had higher odds of subsequent HSCT in both ALL and AML. In a vast country, patients with ALL who live furthest away from their treatment center had higher odds of receiving HSCT, suggesting a preference for HSCT if distance was an issue. Within the Canadian publically funded health care system there was no negative impact with remoteness, race or socioeconomic status on access to transplant care.

Acute lymphoblastic leukemia (ALL) is the most common pediatric oncologic diagnosis, and advances in its treatment have led to progressive improvements in survival. The 4 main components of therapy are remission induction, consolidation, maintenance, and central nervous system-directed therapy, and usually last 2 to 3 years. Treatment intensity based on risk-based stratification is the cornerstone of treatment. Patients with features of more favorable disease are spared the more toxic effects of chemotherapy, whereas more aggressive regimens are reserved for those with higher-risk disease. Prognosis of relapsed pediatric ALL depends primarily on duration of remission and site of relapse.

ARS2 protein is important to early development and cell proliferation, in which ARS2-CASP8AP2 interaction is implicated. However, the predictive significance of ARS2 in childhood acute lymphoblastic leukemia (ALL) is unknown. Here we evaluate the predictive values of ARS2 expression and combined ARS2 and CASP8AP2 expression in relapse. We showed that ARS2 expression in ALL bone marrow samples at initial diagnosis was markedly lower than that in complete remission (CR). Likewise, the levels of ARS2 expression in the patients suffering from relapse were significantly lower than that of patients in continuous CR. Furthermore, low expression of ARS2 was closely correlated to poor treatment response including poor prednisone response and high minimal residual disease (MRD), and the patients with high MRD (≥10(-4)) and low ARS2 were more subject to relapse. The multivariate analyses for relapse free survival and event free survival revealed that ARS2 expression remained an independent prognostic factor after adjusting other risk factors. In addition, combined assessment of ARS2 and CASP8AP2 expression was more accurate to predict relapse, based on which an algorithm composed of ARS2 and CASP8AP2 expression, prednisone response and MRD (day 78) was proposed. Together, ARS2 and CASP8AP2 expressions can precisely predict high-risk of relapse and ALL prognosis.

Cure rates in pediatric acute lymphoblastic leukemia have significantly improved over the past decades. Now, almost 90% of children will survive the disease. The cure rates in adolescents, young adults, and adults have not kept pace with the improvements in younger patients, even though almost an equal proportion of adult patients achieve complete remission as their pediatric counterparts. Differences in treatment regimens might be important. Intensive use of asparaginase has been a key component of successful pediatric therapy. In this review, we focus on the use of asparaginase and the potential of optimizing asparaginase use via monitoring to minimize adverse drug events and improve efficacy of the drug.

Background Acute lymphoblastic leukemia (ALL) is the most well-known sort of leukemia in children. In spite of favorable survival rates, some patients relapse and achieve a poor outcome. Methods We analyzed miR-125b and Bcl-2 expressions in pediatric patients with ALL and evaluated their clinical utility as molecular markers for the prediction of disease outcomes. Results Downregulation of miR-125b and increased Bcl-2 expression levels in pediatric patients with ALL were associated with poor prognosis at diagnosis. At day 28 of induction, miR-125b was significantly increased, whereas Bcl-2 was downregulated. Loss of miR-125b during diagnosis and its elevation after therapy are strongly correlated with short leukemia-free survival and worse survival. Moreover, the combination of miR-125b with Bcl-2 markers can clearly enhance the prediction of the disease outcome. Finally, a univariate analysis highlighted the independent prognostic value of miR-125 in a pediatric patient with ALL. Conclusions miR-125b and Bcl-2 together are potent predictors for the prognosis and, therefore, can be used as therapeutic targets in childhood ALL.

Correct classification and prediction of tumor cells is essential for a successful diagnosis and reliable future treatment. In this study, we aimed at using genetic algorithms for feature selection and proposed silhouette statistics as a discriminant function to distinguish between six subtypes of pediatric acute lymphoblastic leukemia by using microarray with thousands of gene expressions. Our methods have shown a better classification accuracy than previously published methods and obtained a set of genes effective to discriminate subtypes of pediatric acute lymphoblastic leukemia. Furthermore, the use of silhouette statistics, offering the advantages of measuring the classification quality by a graphical display and by an average silhouette width, has also demonstrated feasibility and novelty for more difficult multiclass tumor prediction problems.

The prognostic significance of caspase 8 associated protein 2 (CASP8AP2) in pediatric ALL is controversial. We determined a cut-off of CASP8AP2 expression in bone marrow samples of 39 newly diagnosed patients, and found a significantly poor bone marrow relapse-free survival (p=0.019) in low-expression group and verified it in another cohort of 106 patients (p=0.002). Furthermore, as an independent prognostic factor, CASP8AP2 expression was correlated to minimal residual disease (MRD), and incorporating it with MRD would help to identify patients at greater risk of bone marrow relapse. We also developed an algorithm comprised of clinical risk and CASP8AP2 expression, which could predict bone marrow relapse more accurately.

Because survival with both chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT) approaches to high risk pediatric acute lymphoblastic leukemia (ALL) generally improves through the years, regular comparisons of outcomes with either approach for a given indication are needed to decide when HSCT is indicated. Improvements in risk classification are allowing clinicians to identify patients at high risk for relapse early in their course of therapy. Whether patients defined as high risk by new methods will benefit from HSCT requires careful testing. Standardization and improvement of transplant approaches has led to equivalent survival outcomes with matched sibling and well-matched unrelated donors, however, survival using mismatched and haploidentical donors is generally worse. Trials comparing chemotherapy and HSCT must obtain sufficient data about therapy and stratify the analysis to assess the outcomes of best-chemotherapy with best-HSCT approaches.

Introduction Childhood cancer, as one of the life threatening and most serious health problems, considerably influences the cognitive and social functions of children with cancer and their families; however, surprisingly enough, these children are quite well compatible and even emotionally function better than their peers. Method This issue still remains as a mystery. In this study, the ability of ignoring negative stimuli as a technique of emotion regulation is investigated in children with cancer. For this purpose, 78 children (33 girls and 45 boys aged 3 to 12 years) with pediatric acute lymphoblastic leukemia (ALL) and 89 healthy children (52 girls and 37 boys aged 3 to 12 years) took part in this study. At the first stage, a number of positive, negative and neutral pictures were displayed to children. At the second stage, they were asked to identify these pictures from among a collection of these and other pictures. Result Data analysis indicated that children with cancer, compared with healthy children, could recognize more positive images than negative ones. Conclusion Accordingly, children with cancer, through the neglect of negative stimuli, improve their tolerance, and demonstrate dramatically good adjustment.

In this review, we provide an overview of recent findings from the Northern California Childhood Leukemia Study (NCCLS) on factors related to the immune system including child's vaccination history and measures of child's exposure to infectious agents, namely daycare attendance, infection during infancy, and parental social contact in the work place. We also provide suggestions for the next stages of studies.

The outcome of pediatric acute lymphoblastic leukemia (ALL) has improved dramatically over the last 40 years through a systematic approach of well-designed large trials including use of asparaginase. Although asparaginase has been incorporated with other drugs in adult ALL protocols, it has been associated with more toxicities in older patients resulting in caution in the inclusion of asparaginase-containing regimens for adults. Consequently, to date, no randomized trials with asparaginase have been performed in adults. Furthermore, adult regimens that do not include asparaginase have shown comparable outcomes to regimens with asparaginase, which makes the necessity of asparaginase in adult regimens unclear. There are several other factors which influence the role of asparaginase use in adults, including the level and sustainability of asparagine depletion, schedule, dosing, and form of asparaginase and the consequent toxicities and immunogenicity reactions.

Background and purpose The purpose of this prospective study was to evaluate the hypothesis that magnetization transfer ratio (MTR) histogram analysis of the whole brain could detect early and subtle brain changes nonapparent on conventional magnetic resonance imaging (MRI) in children with acute lymphoblastic leukemia (ALL) receiving methotrexate (MTX) therapy. Materials and methods Subjects in this prospective study comprised 10 children with ALL (mean age, 6 years; range, 0–16 years). In addition to conventional MRI, magnetization transfer images were obtained before and after intrathecal and intravenous MTX therapy. MTR values were calculated and plotted as a histogram, and peak height and location were calculated. Differences in peak height and location between pre- and post-MTX therapy scans were statistically analyzed. Conventional MRI was evaluated for abnormal signal area in white matter. Results MTR peak height was significantly lower on post-MTX therapy scans than on pre-MTX therapy scans (p = 0.002). No significant differences in peak location were identified between pre- and post-chemotherapy imaging. No abnormal signals were noted in white matter on either pre- or post-MTX therapy conventional MRI. Conclusions This study demonstrates that MTR histogram analysis allows better detection of early and subtle brain changes in ALL patients who receive MTX therapy than conventional MRI.

Aberrant expression of tumor suppressor genes WT1 , RB1 , p53 , homozygous deletion of p16 gene and their relationship with expression of oncogenes BCR-ABL , TEL-AML1 , MLL-AF4 , E2A-PBX1 , SIL-TAL1 were determined in bone marrow samples of children with de novo B-lineage ( n = 170) and T-lineage ( n = 25) acute lymphoblastic leukemia (ALL). In contrast to expression of chimeric oncogenes alterations in p16 , WT1 , RB1 and p53 expression were T/B-lineage-unrestricted. Significant association between expression of MLL-AF4 and WT1 , E2A-PBX1 and p53 ; SIL-TAL1 and homozygous deletion of p16 has been demonstrated.

Eighty-eight multi-ethnic Malaysian pediatric acute lymphoblastic leukemia (ALL) patients were screened for the TEL-AML1 rearrangement by reverse transcription-polymerase chain reaction (RT-PCR). Fluorescence in situ hybridization (FISH) was used as an independent screen for 30 cases and to confirm RT-PCR positive cases. Seventeen patients, or 19%, were found to be t(12;21) positive. Ethnically the group comprised 12 Malays, 4 Chinese, and 1 Indian. All patients, including 1 with an unusual blast cell morphology who suffered an early relapse and death, were characteristic TEL-AML1 cases in cell count, age, ALL subset classification, and fusion transcript expressed. This study shows that in Malaysia, TEL-AML1 is found in the same distinct ALL subset and at a similar frequency as in other diverse childhood ALL cohorts.

Pediatric bone marrow evaluation is often challenging, especially for pathologists with more experience evaluating bone marrow specimens from adults. This article reviews the features of several pediatric hematologic malignancies that have been selected because they illustrate the different approach required to evaluate pediatric bone marrow specimens, and highlight potential diagnostic pitfalls. The following topics have been selected for discussion: ancillary studies required for prognostication in pediatric acute lymphoblastic leukemia, the classification of pediatric acute myeloid leukemia, congenital acute leukemia and its distinction from Down syndrome-associated transient myeloproliferative disorder, diagnosis and classification of pediatric myelodysplastic syndromes, and juvenile myelomonocytic leukemia as a distinct disease entity of childhood.

Treatment of pediatric acute lymphoblastic leukemia (ALL) is based on the concept of tailoring the intensity of therapy to a patient's risk of relapse. To determine whether gene expression profiling could enhance risk assignment, we used oligonucleotide microarrays to analyze the pattern of genes expressed in leukemic blasts from 360 pediatric ALL patients. Distinct expression profiles identified each of the prognostically important leukemia subtypes, including T-ALL, E2A-PBX1, BCR-ABL, TEL-AML1, MLL rearrangement, and hyperdiploid >50 chromosomes. In addition, another ALL subgroup was identified based on its unique expression profile. Examination of the genes comprising the expression signatures provided important insights into the biology of these leukemia subgroups. Further, within some genetic subgroups, expression profiles identified those patients that would eventually fail therapy. Thus, the single platform of expression profiling should enhance the accurate risk stratification of pediatric ALL patients.

Nuclear organizer regions (NORs) code for ribosomal RNA and are associated with non-histone nucleoproteins which can be identified by silver staining (AgNORs). AgNORs have been correlated to proliferative activity of tumors and hence may be prognosis-related. The present study evaluates the possible prognostic importance of the AgNORs in tumor cells of patients with pediatric acute lymphoblastic leukemia (ALL). A significant increase in AgNOR counts was observed in ALL patients as compared to normal controls. Further, a significant positive correlation was observed between AgNOR counts and total WBC count at diagnosis. A negative correlation was also observed between AgNOR counts and age of the patients. Logistic regression analysis revealed further correlation between AgNOR counts and disease with an odds ratio of 1.29 (P = 0.03) as compared to normal controls. These results therefore suggest that AgNOR counts may be significant in the evaluation of pediatric ALL.

Remarkable progress has been made in identifying the molecular lesions involved in the pathogenesis of pediatric acute lymphoblastic leukemia. Efforts to clone the genes involved in chromosomal translocations have led to the isolation of a number of novel proto-oncogenes. The biochemical characterization of the encoded products has helped to elucidate important regulatory pathways involved in cellular differentiation, proliferation, or control of cell death, and has helped to define how alterations in these pathways contribute to leukemogenesis. In addition, these efforts have led to the development of molecular-based assays for the identification of the specific molecular lesions. Clinical application of these assays has rapidly led to the realization that molecular lesions can identify distinct patient subgroups with predictable clinical features and responses to therapy. In this review, the emerging role of molecular diagnostics in the clinical management of pediatric patients with acute lymphoblastic leukemia is discussed. (Mol Diagn 1996 Jun;1(2):139-151)

Cytogenetic analysis is of value in predicting clinical outcome of pediatric cases of acute lymphoblastic leukemia (ALL). Hyperdiploidy in these patients has significant impact on therapeutic outcome. Because of the technologic limitations of cytogenetic analysis in determining hyperdiploidy in some of these cases, we devised a method to analyze cytogenetically fixed material for cellular DNA content by standard flow cytometric methods. This technique greatly enhances out ability to interpret the observance of single cell anomalies and assess whether these cells are predictive of clonal stemlines or are a result of random events.