Gary Dahl

Abstract

Single cell network profiling (SCNP) is a multi-parameter flow cytometry technique for simultaneous interrogation of intracellular signalling pathways. Diagnostic paediatric acute myeloid leukaemia (AML) bone marrow samples were used to develop a classifier for response to induction therapy in 53 samples and validated in an independent set of 68 samples. The area under the curve of a receiver operating characteristic curve (AUCROC ) was calculated to be 0·85 in the training set and after exclusion of induction deaths, the AUCROC of the classifier was 0·70 (P = 0·02) and 0·67 (P = 0·04) in the validation set when induction deaths (intent to treat) were included. The highest predictive accuracy was noted in the cytogenetic intermediate risk patients (AUCROC 0·88, P = 0·002), a subgroup that lacks prognostic/predictive biomarkers for induction response. Only white blood cell count and cytogenetic risk were associated with response to induction therapy in the validation set. After controlling for these variables, the SCNP classifier score was associated with complete remission (P = 0·017), indicating that the classifier provides information independent of other clinical variables that were jointly associated with response. This is the first validation of an SCNP classifier to predict response to induction chemotherapy. Herein we demonstrate the usefulness of quantitative SCNP under modulated conditions to provide independent information on AML disease biology and induction response.

View details for DOI 10.1111/bjh.12370

View details for Web of Science ID 000321211300012

View details for PubMedID 23682827

Abstract

The classification of acute myeloid leukemia (AML) has evolved to the most recent World Health Organization (WHO) schema, which integrates genetic, morphologic, and prognostic data into a single system. However, this system was devised using adult data and how this system applies to a pediatric cohort is unknown. Performing a retrospective chart review, we examined our single-center experience with AML in 115 children and classified their leukemia using the WHO 2008 schema. We examined patient samples for mutations of FLT3, NPM1, and CEBPA. Overall survival was calculated within categories. In our pediatric population, most cases of AML had recurrent genetic abnormalities of favorable prognosis. More than 10% of patients in our series were categorized as AML, with myelodysplasia-related changes, an entity not well-described in pediatric patients. In addition, a large proportion of patients were categorized with secondary, therapy-related AML. To our knowledge, this is the first application of the WHO 2008 classification to a pediatric cohort. In comparison to adult studies, AML in the pediatric population shows a distinct distribution within the WHO 2008 classification.

View details for DOI 10.1309/AJCP59WKRZVNHETN

View details for PubMedID 23690127

View details for DOI 10.1038/leu.2012.223

View details for Web of Science ID 000316587300031

View details for PubMedID 22918081

Abstract

Older age has historically been an adverse prognostic factor in pediatric acute myeloid leukemia (AML). To the authors' knowledge, the impact of age relative to that of other prognostic factors on the outcome of patients treated in recent trials is unknown.Clinical outcome and causes of treatment failure of 351 patients enrolled on 3 consecutive protocols for childhood AML between 1991 and 2008 were analyzed according to age and protocol.The more recent protocol (AML02) produced improved outcomes for patients aged 10 years to 21 years compared with 2 earlier studies (AML91 and AML97), with 3-year rates of event-free survival (EFS), overall survival (OS), and cumulative incidence of refractory leukemia or recurrence (CIR) for this group being similar to those of patients aged birth to 9 years: EFS: 58.3% ± 5.4% versus 66.6% ± 4.9% (P = .20); OS: 68.9% ± 5.1% versus 75.1% ± 4.5% (P = .36); and CIR: 21.9% ± 4.4% versus 25.3% ± 4.2% (P = .59). The EFS and OS estimates for patients aged 10 to 15 years overlapped those for patients aged 16 to 21 years. However, the cumulative incidence of toxic death was significantly higher for patients aged 10 to 21 years compared with younger patients (13.2% ± 3.6% vs 4.5% ± 2.0%; P = .028).The survival rate for older children with AML has improved on the results of a recent trial and is now similar to that of younger patients. However, deaths from toxicity remain a significant problem for patients in the older age group. Future trials should focus on improving supportive care while striving to develop more effective antileukemic therapy.

View details for DOI 10.1002/cncr.27659

View details for Web of Science ID 000311911600031

View details for PubMedID 22674050

Abstract

The effect of body mass index (BMI) on the treatment outcomes of children with acute myeloid leukemia (AML) is unclear and needs further evaluation.Children with AML (n = 314) who were enrolled in 4 consecutive St. Jude protocols were grouped according to BMI (underweight, <5th percentile; healthy weight, 5th to 85th percentile; and overweight/obese, ? 85th percentile).Twenty-five patients (8%) were underweight, 86 patients (27.4%) were overweight/obese, and 203 patients (64.6%) had healthy weight. The 5-year overall survival rate of overweight/obese patients (46.5% ± 7.3%) was lower than the rate of patients with healthy weight (67.1% ± 4.3%; P < .001); underweight patients also tended to have lower survival rates (50.6% ± 10.7%; P = .18). In a multivariable analysis that was adjusted for age, leukocyte count, French-American-British classification, and study protocols, patients with healthy weight had the best survival rate among the 3 groups (P = .01). When BMI was considered as continuous variable, patients with lower or higher BMI percentiles had worse survival (P = .03). There was no difference in the occurrence of induction failure or relapse among BMI groups, although underweight and overweight/obese patients had a significantly higher cumulative incidence of treatment-related mortality, especially because of infection (P = .009).An unhealthy BMI was associated with worse survival and more treatment-related mortality in children with AML. Meticulous supportive care with nutritional support and education, infection prophylaxis, and detailed laboratory and physical examination is required for these patients. These measures, together with pharmacokinetics-guided chemotherapy dosing, may improve outcome.

View details for DOI 10.1002/cncr.27640

View details for Web of Science ID 000311306000033

View details for PubMedID 22648558

Abstract

The ability to distinguish clonal B-cell populations based on the sequence of their rearranged immunoglobulin heavy chain (IgH) locus is an important tool for diagnosing B-cell neoplasms and monitoring treatment response. Leukemic precursor B cells may continue to undergo recombination of the IgH gene after malignant transformation; however, the magnitude of evolution at the IgH locus is currently unknown. We used next-generation sequencing to characterize the repertoire of IgH sequences in diagnostic samples of 51 children with B precursor acute lymphoblastic leukemia (B-ALL). We identified clonal IgH rearrangements in 43 of 51 (84%) cases and found that the number of evolved IgH sequences per patient ranged dramatically from 0 to 4024. We demonstrate that the evolved IgH sequences are not the result of amplification artifacts and are unique to leukemic precursor B cells. In addition, the evolution often follows an allelic exclusion pattern, where only 1 of 2 rearranged IgH loci exhibit ongoing recombination. Thus, precursor B-cell leukemias maintain evolution at the IgH locus at levels that were previously underappreciated. This finding sheds light on the mechanisms associated with leukemic clonal evolution and may fundamentally change approaches for monitoring minimal residual disease burden.

View details for DOI 10.1182/blood-2012-05-429811

View details for Web of Science ID 000313111300023

View details for PubMedID 22932801

Abstract

Embryonal tumors are an aggressive subtype of high-grade, pediatric central nervous system (CNS) tumors often with dismal survival rates. The 5-year survival for highest-risk embryonal tumors may be as low as 10 %. We report feasibility and efficacy from our experience using intravenous (IV) cyclophosphamide concurrently with craniospinal radiation (CSI) in high-risk embryonal CNS tumors of childhood. Ten consecutive children (aged: 3.5-15.5 years, median: 10.2 years, six male) with high-risk embryonal tumors, including: large cell/anaplastic medulloblastoma (6), atypical teratoid rhabdoid tumor (1), and leptomeningeal primitive neuroectodermal tumor (3), were treated with IV cyclophosphamide 1 g/M(2) on days 1 and 2 of CSI. Following a median of 36 Gy CSI plus tumor boosts, adjuvant treatment consisted of 21 doses of oral etoposide (7) and alkylator based chemotherapy from five to eight cycles in all. Of the ten patients thus treated, six remain alive with no evidence of disease and four are deceased. Median survival was 3.3 years, with a 3-year progression-free survival of 50 % (5/10). Median follow-up was: 3.3 years (range: 5 months-12.9 years) in the five patients with progression, median time-to-progression was: 1.3 years (range: 1 month-3 years). Median follow-up in the patients without progression is 8.8 years (range: 3-12.9 years). Complications due to adjuvant chemotherapy were typical and included myelosupression (10), necessitating shortened duration of chemotherapy in three, and hemorrhagic cystitis (1). In high-risk embryonal CNS tumors, cyclophosphamide given concurrently with CSI is well tolerated. Early results suggest that a phase II trial is warranted.

View details for DOI 10.1007/s11060-012-0969-2

View details for Web of Science ID 000311208100017

View details for PubMedID 22941430

Abstract

The human leukocyte antigen (HLA) genes are candidate genetic susceptibility loci for childhood acute lymphoblastic leukemia (ALL). We examined the effect of HLA-DP genetic variation on risk and evaluated its potential interaction with 4 proxies for early immune modulation, including measures of infectious exposures in infancy (presence of older siblings, daycare attendance, ear infections) and breastfeeding. A total of 585 ALL cases and 848 controls were genotyped at the HLA-DPA1 and DPB1 loci. Because of potential heterogeneity in effect by race/ethnicity, we included only non-Hispanic white (47%) and Hispanic (53%) children and considered these 2 groups separately in the analysis. Logistic regression analyses showed an increased risk of ALL associated with HLA-DPB1*01:01 (odds ratio [OR] = 1.43, 95% CI, 1.01-2.04) with no heterogeneity by Hispanic ethnicity (P = .969). Analyses of DPB1 supertypes showed a marked childhood ALL association with DP1, particularly for high-hyperdiploid ALL (OR = 1.83; 95% CI, 1.20-2.78). Evidence of interaction was found between DP1 and older sibling (P = .036), and between DP1 and breastfeeding (P = .094), with both showing statistically significant DP1 associations within the lower exposure categories only. These findings support an immune mechanism in the etiology of childhood ALL involving the HLA-DPB1 gene in the context of an insufficiently modulated immune system.

View details for DOI 10.1182/blood-2012-01-404723

View details for Web of Science ID 000311619300021

View details for PubMedID 22923493

Abstract

In acute myeloid leukemia (AML), initial treatment response by morphologic analysis of bone marrow predicts long-term outcome. Response can now be assessed by minimal residual disease (MRD) monitoring with flow cytometry or polymerase chain reaction (PCR). We determined the relation among the results of these approaches and their prognostic value.In the multicenter AML02 study, follow-up bone marrow samples from 203 children and adolescents with newly diagnosed AML were examined by flow cytometry (n = 1,514), morphology (n = 1,382), and PCR amplification of fusion transcripts (n = 508). Results were correlated with treatment outcome.Among 1,215 samples with less than 5% leukemic myeloblasts by morphology, 100 (8.2%) were MRD positive (? 0.1%) by flow cytometry, whereas 96 (57.5%) of the 167 samples with ? 5% blasts were MRD negative. Virtually all (308 of 311; 99.0%) MRD-negative samples by PCR were also MRD negative by flow cytometry. However, only 19 (9.6%) of the 197 PCR-positive samples were flow cytometry positive, with analyses of AML1-ETO and CBF?-MYH11 accounting for most discrepancies, whereas eight of 13 MLL-positive samples had detectable MRD by flow cytometry. MRD by flow cytometry after induction 1 or 2 predicted lower event-free survival and higher relapse rate (P < .001) and was an independent prognostic factor in a multivariable analysis; prediction was not improved by morphologic information or molecular findings.In childhood AML, morphologic assessment of treatment response has limited value if MRD is measured by flow cytometry. MLL fusion transcripts can provide prognostic information in some patients, whereas monitoring of AML1-ETO and CBF?-MYH11 transcripts is largely uninformative.

View details for DOI 10.1200/JCO.2011.41.5323

View details for Web of Science ID 000309653600013

View details for PubMedID 22965955

Abstract

Recent studies suggest that environmental exposures to pesticides, tobacco, and other xenobiotic chemicals may increase risk of childhood acute lymphoblastic leukemia (ALL). We sought to evaluate the role of genes involved in xenobiotic transport and metabolism in childhood ALL risk, both alone and in conjunction with household chemical exposures previously found to be associated with childhood ALL risk.We conducted a population-based epidemiologic study of 377 cases and 448 controls in California, utilizing a haplotype-based approach to evaluate 42 xenobiotic transport and metabolism genes in conjunction with data on self-reported household chemical exposures.We identified significant associations of childhood ALL risk with haplotypes of ABCB1, ARNT, CYP2C8, CYP1A2, CYP1B1, and IDH1. In addition, certain haplotypes showed significant joint effects with self-reported household chemical exposures on risk of childhood ALL. Specifically, elevated risks associated with use of paints in the home (ever) and indoor insecticides (pre-birth) were limited to subjects carrying specific haplotypes of CYP2C8 and ABCB1, respectively.Our results provide support for a role of xenobiotic transport and metabolism pathways in risk of childhood ALL and indicate that genes in these pathways may modulate the risk of disease associated with use of common household chemicals. Additional studies are needed to confirm these findings and localize specific causal variants.

View details for DOI 10.1007/s10552-012-9947-4

View details for Web of Science ID 000306122300016

View details for PubMedID 22674224

Abstract

Relapse remains the leading cause of death in patients with acute myeloid leukaemia (AML). Relatively few new chemotherapy agents have been proven to be effective in this population. We report on a Phase 2 clinical trial using the novel combination of 2-chlorodeoxyadenosine (2-CDA) (8 mg/m² per d x 5 d) plus idarubicin (Ida) (10 mg/m² per d x 3 d). The study involved 109 paediatric patients with AML at first relapse, of whom 104 were available for analysis. The overall response rate was 51% (complete response [CR] + partial response) with a CR rate of 46%. 2-year event-free survival (EFS) and overall survival (OS) were 20% and 26%. The only significant variable in determining response, EFS and OS was duration of initial remission, with patients who had an initial remission >1 year having much worse outcomes overall (response rate 74% vs. 25%, EFS 8% vs. 37% and OS of 16% vs. 39%, P < 0.01 for all). There was an acceptable toxicity profile with one neurological event and no cardiac events observed. The most common grade 3-4 toxicities observed were neutropenia (59%) and thrombocytopenia (68%). This study demonstrated that the novel combination of 2-CDA/Ida was effective and should be considered for incorporation in front line therapy for children with AML.

View details for DOI 10.1111/j.1365-2141.2011.08976.x

View details for Web of Science ID 000300971800010

View details for PubMedID 22512017

Abstract

Hereditary hemochromatosis (HH) is an autosomal-recessive disorder of iron metabolism that most commonly manifests in the fourth or fifth decade of life. Here, we describe a 14-year-old male who presented with high-risk acute lymphoblastic leukemia and previously undiagnosed HH. His treatment course was remarkable for significant therapeutic complications, including iron overload, hepatic failure, cardiac dysfunction, and death. Postmortem testing revealed homozygosity for the C282Y mutation, confirming the diagnosis of HH. Since HH mutations occur commonly in select populations, screening patients with leukemia for HH may better inform treatment decisions regarding chemotherapy, transfusions, and/or iron chelation therapy.

View details for DOI 10.1002/pbc.22829

View details for Web of Science ID 000297641300020

View details for PubMedID 22076832

Abstract

Langerhans cell histiocytosis (LCH) is a rare proliferative disorder that occurs most commonly in the pediatric population as a result of pathological clonal proliferation of Langerhans cells with subsequent damage and destruction to surrounding tissue. Clinically, LCH presents in a variety of ways, which often results in prolonged time to diagnosis and subsequently poorer outcomes. In this case report, the authors describe an unusually early presentation of multisystem LCH in a patient at birth, which resulted in a 5-month delay to diagnosis and treatment. This patient presented both atypically young and with an uncommon initial manifestation of multisystem disease with multiple soft-tissue swellings rather than early skin involvement. Additionally, this patient had an unusual radiographic appearance with biparietal skull destruction on initial skull radiographs and biparietal soft-tissue lesions on CT resembling cephalohematoma at 3 months of age. The clinical and radiological evaluation, pathology, and treatment strategies are discussed, with particular attention paid to the importance of further workup of atypical nonresolving cephalohematomas to prevent disease progression and poorer outcomes.

View details for DOI 10.3171/2010.7.PEDS10149

View details for Web of Science ID 000282244400020

View details for PubMedID 20887116

Abstract

We sought to improve outcome in patients with childhood acute myeloid leukaemia (AML) by applying risk-directed therapy that was based on genetic abnormalities of the leukaemic cells and measurements of minimal residual disease (MRD) done by flow cytometry during treatment.From Oct 13, 2002, to June 19, 2008, 232 patients with de-novo AML (n=206), therapy-related or myelodysplasia-related AML (n=12), or mixed-lineage leukaemia (n=14) were enrolled at eight centres. 230 patients were assigned by block, non-blinded randomisation, stratified by cytogenetic or morphological subtype, to high-dose (18 g/m(2), n=113) or low-dose (2 g/m(2), n=117) cytarabine given with daunorubicin and etoposide (ADE; induction 1). The primary aim of the study was to compare the incidence of MRD positivity of the high-dose group and the low-dose group at day 22 of induction 1. Induction 2 consisted of ADE with or without gemtuzumab ozogamicin (GO anti-CD33 monoclonal antibody); consolidation therapy included three additional courses of chemotherapy or haematopoietic stem-cell transplantation (HSCT). Levels of MRD were used to allocate GO and to determine the timing of induction 2. Both MRD and genetic abnormalities at diagnosis were used to determine the final risk classification. Low-risk patients (n=68) received five courses of chemotherapy, whereas high-risk patients (n=79), and standard-risk patients (n=69) with matched sibling donors, were eligible for HSCT (done for 48 high-risk and eight standard-risk patients). All 230 randomised patients were analysed for the primary endpoint. Other analyses were limited to the 216 patients with AML, excluding those with mixed-lineage leukaemia. This trial is closed to accrual and is registered with ClinicalTrials.gov, number NCT00136084.Complete remission was achieved in 80% (173 of 216 patients) after induction 1 and 94% (203 of 216) after induction 2. Induction failures included two deaths from toxic effects and ten cases of resistant leukaemia. The introduction of high-dose versus low-dose cytarabine did not significantly lower the rate of MRD-positivity after induction 1 (34%vs 42%, p=0.17). The 6-month cumulative incidence of grade 3 or higher infection was 79.3% (SE 4.0) for patients in the high-dose group and 75.5% (4.2) for the low-dose group. 3-year event-free survival and overall survival were 63.0% (SE 4.1) and 71.1% (3.8), respectively. 80% (155 of 193) of patients achieved MRD of less than 0.1% after induction 2, and the cumulative incidence of relapse for this group was 17% (SE 3). MRD of 1% or higher after induction 1 was the only significant independent adverse prognostic factor for both event-free (hazard ratio 2.41, 95% CI 1.36-4.26; p=0.003) and overall survival (2.11, 1.09-4.11; p=0.028).Our findings suggest that the use of targeted chemotherapy and HSCT, in the context of a comprehensive risk-stratification strategy based on genetic features and MRD findings, can improve outcome in patients with childhood AML.National Institutes of Health and American Lebanese Syrian Associated Charities (ALSAC).

View details for DOI 10.1016/S1470-2045(10)70090-5

View details for Web of Science ID 000279019500026

View details for PubMedID 20451454

Abstract

Corticosteroid treatment is an important therapeutic modality for many pediatric medical conditions including acute lymphoblastic leukemia. However, steroid-induced behavioral and mood abnormalities are common and potentially disabling adverse effects that have been widely reported in the pediatric literature. From this case series, we report the efficacy of risperidone in 3 children with acute lymphoblastic leukemia who developed steroid-related mood and psychotic symptoms during treatment with prednisone and dexamethasone. Risperidone is an effective short-term pharmacologic agent for controlling steroid-related psychiatric adverse effects when cessation or dose reduction of steroid therapy is not an option.

View details for DOI 10.1542/peds.2009-1815

View details for Web of Science ID 000277232800060

View details for PubMedID 20385646

Abstract

Valspodar, a non-immunosuppressive analog of cylosporine, is a potent P-glycoprotein (MDR1) inhibitor. As MDR1-mediated efflux of chemotherapeutic agents from leukemic blasts may contribute to drug resistance, a phase 1 study of valspodar combined with mitoxantrone and etoposide in pediatric patients with relapsed or refractory leukemias was performed.Patients received a valspodar-loading dose (2 mg/kg) followed by a 5-day continuous valspodar infusion (8, 10, 12.5, or 15 mg/kg/day) combined with lower than standard doses of mitoxantrone and etoposide. The valspodar dose was escalated using a standard 3 + 3 phase I design.Twenty-one patients were evaluable for toxicity and 20 for response. The maximum tolerated dose (MTD) of valspodar was 12.5 mg/kg/day, combined with 50% dose-reduced mitoxantrone and etoposide. The clearance of mitoxantrone and etoposide was decreased by 64% and 60%, respectively, when combined with valspodar. Dose-limiting toxicities included stomatitis, ataxia, and bone marrow aplasia. Three of 11 patients with acute lymphoblastic leukemia (ALL) had complete responses while no patient with acute myeloid leukemia (AML) had an objective response. In vitro studies demonstrated P-glycoprotein expression on the blasts of 5 of 14 patients, although only 1 had inhibition of rhodamine efflux by valspodar.While this regimen was tolerable, responses in this heavily pretreated population were limited to a subset of patients with ALL.

View details for DOI 10.1002/pbc.22366

View details for Web of Science ID 000275935700009

View details for PubMedID 20209646

Abstract

WT1 is a transcription factor that is aberrantly overexpressed in acute and chronic leukemias. Overexpression of WT1 in pediatric acute myeloid leukemia has been reported, but the prognostic significance is unclear because sample sizes in these studies have been relatively small. WT1 expression was measured by quantitative RT-PCR in samples obtained at diagnosis from 155 pediatric AML patients treated on a cooperative group protocol. Neither overall survival nor event-free survival was correlated with WT1 expression.

View details for DOI 10.1002/pbc.22142

View details for Web of Science ID 000270440900043

View details for PubMedID 19618455

Abstract

Childhood leukemia, which accounts for >30% of newly diagnosed childhood malignancies, is one of the leading causes of death for children with cancer. Genome-wide studies using microarray chips to identify copy number changes in human cancer are becoming more common. In this pilot study, 45 pediatric leukemia samples were analyzed for gene copy aberrations using novel molecular inversion probe (MIP) technology. Acute leukemia subtypes included precursor B-cell acute lymphoblastic leukemia (ALL) (n=23), precursor T-cell ALL (n=6), and acute myeloid leukemia (n=14). The MIP analysis identified 69 regions of recurring copy number changes, of which 41 have not been identified with other DNA microarray platforms. Copy number gains and losses were validated in 98% of clinical karyotypes and 100% of fluorescence in situ hybridization studies available. We report unique patterns of copy number loss in samples with 9p21.3 (CDKN2A) deletion in the precursor B-cell ALL patients, compared with the precursor T-cell ALL patients. MIPs represent an attractive technology for identifying novel copy number aberrations, validating previously reported copy number changes, and translating molecular findings into clinically relevant targets for further investigation.

View details for DOI 10.1016/j.cancergencyto.2009.03.005

View details for Web of Science ID 000268922900002

View details for PubMedID 19602459

Abstract

The optimal form of treatment for children with relapsed or refractory acute promyelocytic leukemia (APL) is unclear. We retrospectively analyzed the results of 32 (11 autologous, 21 allogeneic) hematopoietic stem cell transplants (HSCT) performed for children originally treated on either the Eastern Cooperative Group E2491 Trial or the Cancer and Leukemia Group B C9710 Trial and subsequently diagnosed with relapsed or refractory APL. For autologous HSCT, the incidence of treatment-related mortality (TRM) and relapse was 0% (95% confidence interval [CI], 0%-30%) and 27% (95% CI, 9%-57%), respectively. The 5-year event-free survival (EFS) and overall survival (OS) following autologous HSCT was 73% (95% CI, 43%-91%) and 82% (95% CI, 51%-96%), respectively. For allogeneic HSCT, the incidence of TRM and relapse was 19% (95% CI, 7%-41%) and 10% (95% CI, 2%-30%), respectively. The 5-year EFS and OS following allogeneic HSCT was 71% (95% CI, 50%-86%) and 76% (95% CI, 55%-90%), respectively. There was no significant difference in EFS or OS between autologous and allogeneic HSCT. This data demonstrates that autologous and allogeneic HSCT are both effective therapies for treatment of children with relapsed or refractory APL. Autologous HSCT is associated with a low incidence of TRM, whereas allogeneic HSCT is associated with a low incidence of relapse, suggesting a strong GVL effect against residual APL.

View details for DOI 10.1016/j.bbmt.2008.04.015

View details for Web of Science ID 000256971000013

View details for PubMedID 18541203

Abstract

Gene expression profiling studies have been employed to investigate prognostic subgroups in pediatric acute leukemia. Tissue microarrays (TMAs) are useful for high-throughput analysis of protein expression of target genes in acute leukemia samples and for validation of gene microarray analysis. Using cryopreserved samples of pediatric acute leukemia bone marrow aspirates, we constructed TMA from as few as 1 million cells. Bone marrow core biopsies from the same patients were included on the same TMA for comparison. A panel of 15 immunohistochemical markers typically used for diagnosis as well as those targeting recently characterized, prognostically relevant molecules of interest in pediatric acute leukemia was used to evaluate protein expression. Staining results confirm that suspension cells from bone marrow aspirates can be effectively used to derive protein expression data from multiple cases simultaneously with comparable efficacy to that of biopsy tissue. This method allows for new markers of diagnostic, prognostic, or therapeutic importance to be screened on large numbers of study patients. Furthermore, this technique may facilitate the inclusion of small samples, aspirates, and body fluids in large-scale studies of protein expression in clinical trials and protocols in which tissue biopsies are often unavailable.

View details for DOI 10.2350/07-04-0253.1

View details for Web of Science ID 000259353300005

View details for PubMedID 17990919

Abstract

We compared the antitumor activities of the multitargeted tyrosine kinase inhibitors imatinib, sorafenib, and sunitinib to determine which inhibitor is best suited to be used for the treatment of acute myelogenous leukemia (AML). In nine human AML cell lines, sorafenib and sunitinib were more potent inhibitors of cellular proliferation than imatinib (IC50, 0.27 to >40, 0.002-9.1, and 0.007-13 micromol/L for imatinib, sorafenib, and sunitinib, respectively). Sorafenib and sunitinib were potent inhibitors of cells with fms-like tyrosine kinase 3 internal tandem duplication (IC50, 2 and 7 nmol/L) and c-KIT N822K mutations (IC50, 23 and 40 nmol/L). In four cell lines (MV4-11, Kasumi-1, KG-1, and U937) that spanned a range of drug sensitivities, sorafenib and sunitinib had similar activity in apoptosis and cell cycle assays, except that sunitinib did not promote apoptosis in U937 cells. Both drugs inhibited mitogen-activated protein kinase signaling but had no effect on AKT signaling in most of the cell lines tested. Sorafenib was substantially more bound than sunitinib in human plasma (unbound fraction, 0.59% versus 8.4%) and cell culture medium (unbound fraction, 1.3% versus 39%), indicating that sorafenib was more potent than sunitinib and that unbound sorafenib concentrations with activity against most AML cell lines are achievable in vivo. There was more intracellular accumulation of sorafenib than of sunitinib and imatinib in AML cells. Between 1 and 10 micromol/L, sorafenib inhibited the proliferation of six of nine primary AML blast samples by > or =50%. Our results highlight the pharmacologic features of sorafenib that may provide it an advantage in the treatment of AML.

View details for DOI 10.1158/1535-7163.MCT-07-2218

View details for Web of Science ID 000255913900012

View details for PubMedID 18483300

Abstract

We describe a 2-year-old female with a completely resected cerebral pilocytic astrocytoma who subsequently developed B-progenitor acute lymphoblastic leukemia (ALL). Her father and paternal uncle were previously diagnosed with glioblastoma multiforme. Sequence analysis of the patient's p53 gene revealed a novel germline three base-pair deletion (339_341delCTT) in exon 4, resulting in removal of an evolutionarily conserved phenylalanine amino acid residue at codon 113. The same mutation was found in the patient's two clinically unaffected siblings. The in-frame deletion we describe has not previously been reported and adds to our understanding of the biologic effects of p53 gene mutation in Li-Fraumeni syndrome (LFS).

View details for DOI 10.1002/pbc.21247

View details for Web of Science ID 000253661200049

View details for PubMedID 17554785

Abstract

To determine the outcomes, with particular attention to toxicity, of children with Down syndrome (DS) and acute myeloid leukemia (AML) treated on Pediatric Oncology Group (POG) protocol 9421.Children with DS and newly diagnosed AML (n = 57) were prospectively enrolled onto the standard-therapy arm of POG 9421 and were administered five cycles of chemotherapy, which included daunorubicin 135 mg/m(2) and mitoxantrone 80 mg/m(2). Outcomes and toxicity were evaluated prospectively and were compared with the non-DS-AML cohort (n = 565). A retrospective chart review was performed to identify adverse cardiac events.In the DS-AML group, 54 patients (94.7%) entered remission. One experienced induction failure and two died. Of the 54 who entered remission, three relapsed and six died as a result of other causes. The remission induction rate was similar in the non-DS-French-American-British (FAB) M7 (91.7%) and non-DS-non-M7 (89.3%) groups. The 5-year overall survival was significantly better in the DS-AML group (78.6%) than in the non-DS-M7 (36.3%) or the non-DS-non-M7 (51.8%) groups (P < .001). No age-related difference in 5-year, event-free survival was seen between patients younger than 2 years (75.8%) and those aged 2 to 4 years (78.3%). Symptomatic cardiomyopathy developed in 10 patients (17.5%) with DS-AML during or soon after completion of treatment; three died as a result of congestive heart failure.The POG 9421 treatment regimen was highly effective in both remission induction and disease-free survival for patients with DS-AML. However, there was a high incidence of cardiomyopathy, which supports current strategies for dose reduction of anthracyclines in this patient population.

View details for DOI 10.1200/JCO.2007.13.2209

View details for Web of Science ID 000254177200015

View details for PubMedID 18202418

Abstract

Given pediatric cancer patients are living into adulthood, parents and patients need to be informed about fertility-related side effects of their particular treatment.We surveyed 97 parents of pediatric patients of all ages as well as 37 adolescent patients of 14 years or older who were presented for care at the Lucile Packard Children's Hospital (LPCH) at the Stanford University Medical Center. We estimated the potential infertility risk (low, intermediate, and high) based on the child's treatment regimen.In contrast to our hypothesis, the majority of parents in all three risk categories were concerned about fertility-related side effects of cancer treatment. Many parents with children at low risk were concerned (58.3%) whereas not all parents with children at intermediate or high risk were concerned, 61.5% and 73.3% respectively, P = 0.43. Indeed, over 50% of all parents were erroneously concerned that cancer therapies cause DNA damage to their child's eggs (or sperm). Only 29.9% of parents were satisfied with the amount of information received. Similar patterns were seen among the adolescent patient sample.Parents of pediatric cancer patients and teenage patients have concerns about fertility-related side effects regardless of treatment received. Targeted education about infertility risk before and after treatment can address these gaps.

View details for DOI 10.1002/pbc.21261

View details for Web of Science ID 000251410400015

View details for PubMedID 17514741

Abstract

HBL and HCC are the most common hepatic malignancies in children. The role of OLT in children with HCC is still a matter of debate. The aim of this study was to review our experience of OLT for HCC. Medical records of patients (<18 yr) who underwent OLT for HCC were reviewed and compared to children who underwent OLT for HBL and for indications other than malignancy. There were 25 patients: HCC (10 cases) and HBL (15 cases). The actuarial patient survival for HCC at one and five yr was 100% and 83.3%, for the HBL group the survival was 86.7% at both one and five yr, and for indications (n=377) other than malignancy the patient survival for pediatric OLT at our center was 87.7% and 84.7% at one and five yr, respectively. The actuarial recurrence free survival at five yr was 83.3% for HCC and 66.8% for HBL. In conclusion, OLT is a good therapeutic modality for children with HCC and HBL.

View details for DOI 10.1111/j.1399-3046.2007.00751.x

View details for Web of Science ID 000249004000015

View details for PubMedID 17663690

Abstract

While the disease-free survival of acute promyelocytic leukemia (APML) now approaches 75%, some children continue to experience relapses, and questions remain as to the optimal management of these patients. We describe two young children who experienced combined relapses in the bone marrow and extramedullary locations following hematopoietic stem cell transplantation (HSCT). An induction regimen, consisting of all-trans retinoic acid (ATRA), methotrexate, and 6-mercaptopurine (6MP), successfully and safely achieved hematologic remission in one patient and molecular remission in the other. These cases demonstrate that there is a role for ATRA plus differentiating chemotherapy other than arsenic trioxide in the treatment of relapsed APML.

View details for DOI 10.1002/pbc.20592

View details for Web of Science ID 000245195200019

View details for PubMedID 16123994

Abstract

Despite decreases in overall mortality following bone marrow transplantation (BMT), a number of complications such as neurotoxicity have been described and often associated with immunosuppressive agents. The syndrome of reversible posterior leukoencephalopathy has been described in patients receiving cyclosporin and FK-506. We report here a subset of children who developed a syndrome of previously undescribed irreversible leukoencephalopathy following allogeneic BMT.Between 1996 and 2002, 138 pediatric patients received an allogeneic BMT at Lucile Salter Packard Children's Hospital at Stanford. Six cases of irreversible leukoencephalopathy were observed. Cases were defined as children who exhibited progressive and continued, severe neurologic deterioration lasting greater than 2 weeks and consistent with non-localizing, central nervous system abnormalities. Medical records and magnetic resonance images (MRIs) were reviewed.Median age of the affected patients at BMT was 7.8 years. All six received cyclosporine, and [corrected] one had elevated drug levels. Encephalopathy occurred at a median of 53 days (range 14-77) following BMT. Symptoms at onset of leukoenceophalopathy included confusion and altered mental status, sluggish pupillary responses, abnormal movements, and seizures. Two patients died during their neurologic decline. Four patients remain alive with persistent encephalopathy. MRI showed abnormalities in all patients including periventricular or subcortical white matter involvement in all, and basal ganglia lesions in three.We report a syndrome of irreversible neurologic deficits and cerebral white matter abnormalities following allogeneic BMT, yet not associated with elevated cyclosporin levels. A precise mechanism for this syndrome is lacking and warrants further consideration.

View details for DOI 10.1002/pbc.20731

View details for Web of Science ID 000242875800016

View details for PubMedID 16365853

Abstract

Given the higher survival rates of childhood cancer, health care providers must be aware of the side effects of cancer therapies to educate patients and provide appropriate interventions to reduce cancer-related morbidity. To understand the current practices and attitudes in a pediatric hematology/oncology clinic, health care providers were surveyed regarding fertility issues pertinent to their patient care. PARTICIPANTS AND INSTRUMENTS: In this study, 93.8% (30/32) health care providers in one pediatric hematology/oncology department completed a 44-item survey assessing knowledge, current practices, obstacles to current practices, perceptions of patient differences, and improvements to future practice.The majority of health care providers were aware of the adverse effects of alkylating agents (90.7%) and of abdominal and pelvic radiation (100.0%) on fertility. However, only half were aware of gender differences in gonadotoxicity (50.0%) or knowledgeable of current research and technology in fertility preservation (53.3%). While only 34.6% of providers currently consulted with specialists, nearly all (92.8%) indicated a desire to do so in the future, but 64.3% indicated difficulties in finding proper facilities and specialists for their patients. Almost all (96.6%) agreed that providers and patient families need more information regarding the effects of cancer therapy on fertility.Surveyed pediatric oncology providers considered fertility to be an important issue for childhood cancer patients and desired more resources regarding effects on fertility and fertility preservation. Greater communication needs to be established between pediatric oncology providers and specialists in reproductive medicine and endocrinology to ensure adequate professional collaboration and patient referrals.

View details for DOI 10.1002/pbc.20814

View details for Web of Science ID 000242425000015

View details for PubMedID 16572406

View details for DOI 10.1158/1078-0432.CCR-06-0651

View details for Web of Science ID 000239834400001

View details for PubMedID 16914562

Abstract

A unique transient leukemia (TL) has been described in newborns with Down syndrome (DS; or trisomy 21 mosaics). This leukemia has a high incidence of spontaneous remission; however, early death and subsequent development of acute megakaryoblastic leukemia (AMKL) have been reported. We prospectively evaluated 48 infants with DS and TL to determine the natural history and biologic characteristics of this disease, identify the clinical characteristics associated with early death or subsequent leukemia, and assess the incidence of subsequent leukemia. Blast cells associated with TL in DS infants exhibited FAB M(7) morphology and phenotype. Most infants (74%) had trisomy 21 (or mosaicism) as the only cytogenetic abnormality in the blast cells. Most children were able to spontaneously clear peripheral blasts (89%), normalize blood counts (74%), and maintain a complete remission (64%). Early death occurred in 17% of infants and was significantly correlated with higher white blood cell count at diagnosis (P < .001), increased bilirubin and liver enzymes (P < .005), and a failure to normalize the blood count (P = .001). Recurrence of leukemia occurred in 19% of infants at a mean of 20 months. Development of leukemia was significantly correlated with karyotypic abnormalities in addition to trisomy 21 (P = .037). Ongoing collaborative clinical studies are needed to determine the optimal role of chemotherapy for infants at risk for increased mortality or disease recurrence and to further the knowledge of the unique biologic features of this TL.

View details for DOI 10.1182/blood-2005-06-2448

View details for Web of Science ID 000238305400013

View details for PubMedID 16469874

Abstract

Secreted protein, acidic and rich in cysteine (SPARC), is a matricellular glycoprotein with growth-inhibitory and antiangiogenic functions. Although SPARC has been implicated as a tumor suppressor in humans, its function in normal or malignant hematopoiesis has not previously been studied. We found that the leukemic cells of AML patients with MLL gene rearrangements express low to undetectable amounts of SPARC whereas normal hematopoietic progenitors and most AML patients express this gene. SPARC RNA and protein levels were also low or undetectable in AML cell lines with MLL translocations. Consistent with its tumor suppressive effects in various solid tumor models, exogenous SPARC protein selectively reduced the growth of cell lines with MLL rearrangements by inhibiting cell cycle progression from G1 to S phase. The lack of SPARC expression in MLL-rearranged cell lines was associated with dense promoter methylation. However, we found no evidence of methylation-based silencing of SPARC in primary patient samples. Our results suggest that low or absent SPARC expression is a consistent feature of AML cells with MLL rearrangements and that SPARC may function as a tumor suppressor in this subset of patients. A potential role of exogenous SPARC in the therapy of MLL-rearranged AML warrants further investigation.

View details for DOI 10.1038/sj.leu.2404102

View details for Web of Science ID 000235537800007

View details for PubMedID 16424866

Abstract

The vascular endothelium plays a central role in the regulation of arterial vasomotor tone, releasing nitric oxide for vasodilation. Endothelial-dependent vasodilation can be assessed in vivo, using high resolution ultrasound to measure changes in diameter of the brachial artery. Animal studies have demonstrated that anthracyclines can damage the endothelium and impair the vasodilatory response of arteries; however, there are no comparable data in humans. This is a pilot study assessing endothelial toxicity from anthracyclines in pediatric cancer patients.Fourteen control patients and 14 cancer patients (4 to 21 years) were studied. Cancer patients had completed chemotherapy containing no less than 300 mg/m2 of anthracyclines 2 to 60 months before study. Brachial artery diameters were measured at rest and 1 minute after blood pressure cuff occlusion. Brachial artery reactivity (BAR) was calculated as percent change between baseline and after cuff deflation measurements. Results were compared using unpaired, two-tailed t-test.Baseline characteristics, including age, percentage of females, blood pressure, and resting vessel diameters were similar between the two groups. BAR in the controls averaged 6.7% with a standard deviation (SD) of 3.3%, while BAR in patients receiving anthracyclines averaged 3.8% with an SD of 3.4%, demonstrating a significant decrease (P < .05) in vasomotor reactivity in the treated group.These results suggest that anthracyclines cause impaired endothelial function, an important and newly recognized toxicity. Since endothelial dysfunction is an early event in atherogenesis, there may be important clinical implications from these findings. Further study is required to confirm these preliminary results in a larger cohort.

View details for DOI 10.1200/JCO.2005.03.5956

View details for Web of Science ID 000235469700017

View details for PubMedID 16484703

Abstract

Relapse is a major obstacle in the cure of acute myeloid leukemia (AML). The Pediatric Oncology Group AML Study 9421 tested 2 different strategies to improve event-free survival (EFS) and overall survival (OS). Patients were randomized to receive standard-dose DAT (daunorubicin, cytarabine, and thioguanine) or high-dose DAT during induction. To interfere with P-glycoprotein (P-gp)-dependent drug efflux, the second randomization tested the benefit of cyclosporine (CsA) added to consolidation chemotherapy. Of the 282 children randomly assigned to receive standard DAT induction, 248 (87.9%) achieved remission compared to 253 (91%) of the 278 receiving high-dose DAT (P = ns). Children with HLA-identical sibling donors who achieved a complete remission received an allogeneic bone marrow transplant as consolidation. For the 83 patients receiving a matched related donor bone marrow transplantation (BMT), the 3-year disease-free survival (DFS) is 67%. Of the 418 children who achieved remission and went on to consolidation with and without CsA, the DFS was 40.6% and 33.9%, respectively (P = .24). Overexpression of P-gp was infrequent (14%) in this pediatric population. In this study, intensifying induction with high-dose DAT and the addition of CsA to consolidation chemotherapy did not prolong the durations of remission or improve overall survival for children with AML.

View details for DOI 10.1128/blood-2004-08-3218

View details for Web of Science ID 000235296100018

View details for PubMedID 16254147

Abstract

The survival of children with CNS tumors approaches 70%, yet health-related quality of life (HRQOL) has not been investigated rigorously in this population. We aimed to show that universal assessment of HRQOL could be obtained easily by using the PedsQL 4.0 and to provide a composite profile of their daily lives.The PedsQL was administered to all patients seen in the neuro-oncology clinic at Lucile Packard Children's Hospital (Palo Alto, CA) from December 2001, to September 2002. Patients were compared with healthy controls by using two-sided t tests to evaluate statistically significant differences.One hundred thirty-four patients (73 male; mean age +/- standard deviation, 11.8 +/- 5.4 years; 55 had low-grade glioma, 32 had medulloblastoma/primitive neuroectodermal tumor/embryonal tumor, 17 had malignant astrocytoma, nine had germ-cell tumor, and 21 had other types of tumors) were assessed, each in less than 20 minutes. Scores on both child and parent-proxy reports for the total HRQOL, psychosocial, physical, emotional, social, and school-functioning scales were all significantly lower than controls (P < .01). Patients with low-grade glioma were reported to have the highest total HRQOL. Children receiving radiation therapy (XRT) but no chemotherapy had significantly lower total, psychosocial, emotional, and social functioning than those receiving other treatments, including XRT plus chemotherapy.The PedsQL can be used to assess HRQOL rapidly and easily in children with CNS tumors, who have significantly worse HRQOL than healthy children. Children receiving XRT fare worse overall; chemotherapy added to XRT does not seem to worsen HRQOL. Assessment of HRQOL should be included as an outcome in future clinical trials.

View details for DOI 10.1200/JCO.2005.10.190

View details for Web of Science ID 000231371700020

View details for PubMedID 16110009

Abstract

Fms-like tyrosine kinase 3 (FLT3) mutations are associated with unfavorable outcomes in children with acute myeloid leukemia (AML). We used DNA microarrays to identify gene expression profiles related to FLT3 status and outcome in childhood AML. Among 81 diagnostic specimens, 36 had FLT3 mutations (FLT3-MUs), 24 with internal tandem duplications (ITDs) and 12 with activating loop mutations (ALMs). In addition, 8 of 19 specimens from patients with relapses had FLT3-MUs. Predictive analysis of microarrays (PAM) identified genes that differentiated FLT3-ITD from FLT3-ALM and FLT3 wild-type (FLT3-WT) cases. Among the 42 specimens with FLT3-MUs, PAM identified 128 genes that correlated with clinical outcome. Event-free survival (EFS) in FLT3-MU patients with a favorable signature was 45% versus 5% for those with an unfavorable signature (P = .018). Among FLT3-MU specimens, high expression of the RUNX3 gene and low expression of the ATRX gene were associated with inferior outcome. The ratio of RUNX3 to ATRX expression was used to classify FLT3-MU cases into 3 EFS groups: 70%, 37%, and 0% for low, intermediate, and high ratios, respectively (P < .0001). Thus, gene expression profiling identified AML patients with divergent prognoses within the FLT3-MU group, and the RUNX3 to ATRX expression ratio should be a useful prognostic indicator in these patients.

View details for DOI 10.1182/blood-2004-12-4449

View details for Web of Science ID 000224795700014

View details for PubMedID 15251987

Abstract

We performed a phase I trial of intrathecal (IT) liposomal cytarabine (DepoCyt; Enzon Pharmaceuticals, Piscataway, NJ and SkyePharma Inc, San Diego, CA) to determine the maximum-tolerated dose, the dose-limiting toxicities, and the plasma and CSF pharmacokinetics of IT lipsomal cytarabine in children >/= 3 years of age with advanced meningeal malignancies.Eighteen assessable patients received IT liposomal cytarabine through either an indwelling ventricular access device or via lumbar puncture. Liposomal cytarabine was given once every 2 weeks during induction, once every 4 weeks during consolidation, and once every 8 weeks during the maintenance phase of treatment. The initial dose was 25 mg, with subsequent escalations to 35 and 50 mg. CSF pharmacokinetic samples were obtained in a subset of patients.Arachnoiditis, characterized by fever, headache, nausea, vomiting, and back pain was noted in the first two patients at the 25 mg dose level. Therefore, subsequent patients were treated with dexamethasone, beginning the day of liposomal cytarabine administration and continuing for 5 days. Headache (grade 3) was dose limiting in two of eight patients enrolled at the 50 mg dose level. Eight of the 14 patients assessable for response demonstrated evidence of benefit manifest as prolonged disease stabilization or response.The maximum-tolerated dose and recommended phase II dose of liposomal cytarabine in patients between the ages of 3 and 21 years is 35 mg, administered with dexamethasone (0.15 mg/kg/dose, twice a day for 5 days). A phase II trial of IT liposomal cytarabine in children with CNS leukemia in second or higher relapse is in development.

View details for DOI 10.1200/JCO.2004.01.046

View details for Web of Science ID 000224281600013

View details for PubMedID 15459213

Abstract

The potential etiologic role of household pesticide exposures was examined in the Northern California Childhood Leukemia Study. A total of 162 patients (0-14 years old) with newly diagnosed leukemia were rapidly ascertained during 1995-1999, and 162 matched control subjects were randomly selected from the birth registry. The use of professional pest control services at any time from 1 year before birth to 3 years after was associated with a significantly increased risk of childhood leukemia [odds ratio (OR) = 2.8; 95% confidence interval (CI), 1.4-5.7], and the exposure during year 2 was associated with the highest risk (OR = 3.6; 95% CI, 1.6-8.3). The ORs for exposure to insecticides during the 3 months before pregnancy, pregnancy, and years 1, 2, and 3 were 1.8 (95% CI, 1.1-3.1), 2.1 (95% CI, 1.3-3.5), 1.7 (95% CI, 1.0-2.9), 1.6 (95% CI, 1.0-2.7), and 1.2 (95% CI, 0.7-2.1), respectively. Insecticide exposures early in life appear to be more significant than later exposures, and the highest risk was observed for exposure during pregnancy. Additionally, more frequent exposure to insecticides was associated with a higher risk. In contrast to insecticides, the association between herbicides and leukemia was weak and nonsignificant. Pesticides were also grouped based on where they were applied. Exposure to indoor pesticides was associated with an increased risk, whereas no significant association was observed for exposure to outdoor pesticides. The findings suggest that exposure to household pesticides is associated with an elevated risk of childhood leukemia and further indicate the importance of the timing and location of exposure.

View details for Web of Science ID 000177893800039

View details for PubMedID 12204832

Abstract

The purpose of this study was to assess the effect of the multidrug resistance modulator cyclosporine (CsA) on the pharmacokinetics of etoposide and mitoxantrone in children with de novo acute myeloid leukemia (AML). Serial blood samples for pharmacokinetic studies were obtained in 38 children over a 24-h period following cytotoxin treatment with or without CsA on days 1 and 4. Drug concentrations were quantitated using validated HPLC methods, and pharmacokinetic parameters were determined using compartmental modeling with an iterative two-stage approach, implemented on ADAPT II software. Etoposide displayed a greater degree of interindividual variability in clearance and systemic exposure than mitoxantrone. With CsA treatment, etoposide and mitoxantrone mean clearance declined by 71% and 42%, respectively. These effects on clearance, in combination with the empiric 40% dose reduction for either cytotoxin, resulted in a 47% and 12% increases in the mean AUC for etoposide and mitoxantrone, respectively. There were no differences in the rates of stomatitis or infection between the two groups. CsA treatment resulted in an increased incidence of hyperbilrubinemia, which rapidly reversed upon conclusion of drug therapy. The variability observed in clearance, combined with the empiric 40% dose reduction of the cytotoxins, resulted in statistically similar systemic exposure and similar toxicity.

View details for DOI 10.1038/sj/leu/2402455

View details for Web of Science ID 000175631200020

View details for PubMedID 11986955

Abstract

To investigate the prognostic significance of surveillance neuroimaging for detection of relapse among children with malignant brain tumors.A historical cohort study examined all children who experienced relapse from 1985 to 1999 on one of 10 Pediatric Oncology Group trials for malignant glioma, medulloblastoma, or ependymoma.For all 291 patients (median age at diagnosis, 8.2 years), median time to first relapse was 8.8 months (range, 0.6 to 115.6 months). Ninety-nine relapses were radiographic, and 192, clinical; median time to relapse was 15.7 versus 6.6 months, respectively (P = .0001). When stratified by pathology, radiographic and clinical groups showed differences in median time to relapse for malignant glioma (7.8 v 4.3 months, respectively; P = .041) and medulloblastoma (23.6 v 8.9 months, respectively; P = .0006) but not ependymoma (19.5 v 13.3 months, respectively; P = .19). When stratified by early (< 8.8 months) or late (> or = 8.8 months) time to relapse, 115 early relapses were clinical, and 32, radiographic; for late relapses, 77 were clinical, and 67, radiographic (P = .001). Overall survival (OS) from relapse was significantly longer for radiographic compared with clinical detection (median, 10.8 months; 1-year OS, 46% v median, 5.5 months; 1-year OS, 33%; P = .002), but this trend did not retain significance when analyzed by pathology subgroups.Surveillance neuroimaging detects a proportion of asymptomatic relapses, particularly late relapses, and may provide lead time for other therapies on investigational trials. During the first year after diagnosis, radiographic detection of asymptomatic relapse was infrequent. A prospective study is needed to formulate a rational surveillance schedule based on the biologic behavior of these tumors.

View details for Web of Science ID 000171901100006

View details for PubMedID 11689581

Abstract

The authors report the use of a cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (CHOP)-based chemotherapy regimen in treating six children with posttransplantation lymphoproliferative disorder (PTLD) that developed after solid organ transplantation.The chemotherapy regimen consisted of a 29-day induction with CHOP and then as many as 15 cycles of maintenance therapy using methotrexate and cytarabine alternating with vincristine, adriamycin, mercaptopurine, and prednisone.All patients attained remission. One patient died of sepsis while in remission. Four of the five remaining patients have been followed-up in remission for as long as 8 years without losing the graft. One of the patients experienced relapse after completing therapy and subsequently died with disease.The authors conclude that pediatric patients with PTLD after solid organ transplantation that fails conservative management can be treated successfully with CHOP-based chemotherapy.

View details for Web of Science ID 000171516000011

View details for PubMedID 11878581

View details for Web of Science ID 000089577700013

View details for PubMedID 11025481

Abstract

To determine the remission rate and toxicity of mitoxantrone, etoposide, and cyclosporine (MEC) therapy, multidrug resistance-1 (MDR1) status, and steady-state cyclosporine (CSA) levels in children with relapsed and/or refractory acute myeloid leukemia.MEC therapy consisted of mitoxantrone 6 mg/m(2)/d for 5 days, etoposide 60 mg/m(2)/d for 5 days, and CSA 10 mg/kg for 2 hours followed by 30 mg/kg/d as a continuous infusion for 98 hours. Because of pharmacokinetic interactions, drug doses were decreased to 60% of those found to be effective without coadministration of CSA. MDR1 expression was evaluated by reverse transcriptase polymerase chain reaction, flow cytometry, and the ability of CSA at 2.5 micromol/L to increase intracellular accumulation of (3)H-daunomycin in blasts from bone marrow specimens.The remission rate was 35% (n = 23 of 66). Overall, 35% of patients (n = 23) achieved complete remission (CR), 12% of patients (n = 8) achieved partial remission, and 9% of patients (n = 6) died of infection. Exposure to CSA levels of greater than 2,400 ng/mL was achieved in 95% of patients (n = 56 of 59). Toxicities included infection, cardiotoxicity, myelosuppression, stomatitis, and reversible increases in serum creatinine and bilirubin. In most who had relapsed while receiving therapy or whose induction therapy had failed, response was not significantly different for MDR1-positive and MDR1-negative patients.Serum levels of CSA capable of reversing multidrug resistance are achievable in children with acceptable toxicity. The CR rate of 35% achieved in this study is comparable to previously reported results using standard doses of mitoxantrone and etoposide. The use of CSA may have improved the response rate for the MDR1-positive patients so that it was not different from that for the MDR1-negative patients.

View details for Web of Science ID 000086873900008

View details for PubMedID 10784627

Abstract

The goal of this multi-institutional retrospective study of children with intracranial ependymoma was to identify risk factors associated with unfavorable overall survival (OS) and event-free survival (EFS).Clinical data, including demographics, tumor location, spread, histology, details of surgery, radiation treatment, and chemotherapy were collected. Clinical characteristics and univariate and multivariate analyses of risk factors for OS and EFS are presented.Eleven U.S. institutions contributed 83 patients treated from 1987 to 1991. The OS at 5 and 7 years was 57% and 46%, and EFS at 5 and 7 years was 42% and 33%. Patients 3 years of age or younger differed from the older group by more common infratentorial location, less common gross total resection (GTR), and postoperative use of chemotherapy rather than radiation. This younger group of patients had worse survival (P < 0.01) than the older age group. Other than young age, less than GTR and World Health Organization (WHO) II grade 3 histology were significant adverse risk factors for EFS in univariate and multivariate analyses. OS shared the same adverse risk factors except for histology in multivariate analysis, which was only of borderline significance (P = 0.05). Progression at the original tumor location, present in 89% of patients, was the major pattern of tumor recurrence. Adjuvant chemotherapy in the group older than 3 years or craniospinal radiation in M0 patients did not significantly change EFS.Adverse outcome in childhood intracranial ependymoma is related to age (3 years or younger), histology (grade 3), and degree of surgical resection (less than GTR). New approaches, particularly for local tumor control in younger patients, are needed to improve survival.

View details for Web of Science ID 000080625600007

View details for PubMedID 10363853

Abstract

Although the Bcl-2 protein inhibits apoptosis (programmed cell death) of lymphoid cells induced by a variety of stimuli, its effects on myeloid cell short- and long-term survival after chemotherapy are less defined. We sought to elucidate the short- and long-term effect of Bcl-2 in a well-studied myeloid cell line (HL-60) treated with specific anti-AML chemotherapy. HL-60 cells overexpressing Bcl-2 (HL-60/BCL-2) were more resistant than parental HL-60 cells to multiple chemotherapeutic agents in short-term apoptosis and viability assays. Significantly, HL-60/BCL-2 cells retained greater long-term proliferative capacity than HL-60 cells when treated with low doses of doxorubicin. To assess the importance of Bcl-2 expression in pediatric AML we correlated clinical outcome and levels of Bcl-2 protein in 22 patient specimens. The correlation did not achieve statistical significance with patient response to chemotherapy or long-term outcome, suggesting that analysis of larger numbers of patient samples would not be useful. Our study suggests that although Bcl-2 clearly promotes short and long-term survival in a myeloid cell line, measurement of Bcl-2 levels alone are not sufficient to be of prognostic significance in pediatric AML.

View details for Web of Science ID 000073169100013

View details for PubMedID 9585084

Abstract

Because of their life-long requirement for immunosuppressive therapy, neoplastic disorders could represent a significant threat to long-term survival in infants and children after heart transplantation. This study determined the incidence and clinical spectrum of neoplastic disorders in 80 pediatric patients who underwent heart transplantation between 1974 and 1992.Follow-up ranged from 6 to 189 months (mean, 50.0 months). Tumors occurred in 10 patients (12.5%). Time to detection ranged from 3.3 to 139.2 months (mean, 52.7 months). Tumor incidence was greatest in 9 patients transplanted before the cyclosporine era (44%) compared with the subsequent 71 patients (8.5%, P < .05). There was no increase in risk related to sex, age, underlying disease, or blood type; however, patients with tumors received higher initial doses of cyclosporine and prednisone and had more rejection episodes in the first 3 months (P < .05). There was an increased risk associated with anti-thymocyte globulin (33%, P < .05) but not with OKT3 (6%, P = NS). There were eight lymphoproliferative disorders (four B-cell, one T-cell, three not determined) and one hepatocellular and one squamous cell carcinomas. Six cases of lymphoproliferative disorder had in situ evidence of Epstein-Barr virus. Patients were treated by reducing immunosuppression (7), radiotherapy (2), and chemotherapy (1). There were five deaths: two tumor related and the others due to rejection, renal failure, and infection. Of 5 survivors, 1 had tumor recurrence 4 years after diagnosis, and 4 are disease free.Tumors represent a small but serious long-term risk to pediatric heart transplant recipients. The incidence in children transplanted in the cyclosporine era is similar to that in adults, and the majority of tumors are lymphoproliferative disorders that often regress by reducing immunosuppression.

View details for PubMedID 8222159