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1.  Central Nervous System Disease in Hematological Malignancies: Historical Perspective and Practical Applications 
Seminars in oncology  2009;36(4 Suppl 2):S2-S16.
Acute lymphoblastic leukemia (ALL) 5-year survival rates are approaching 90% in children and 50% in adults who are receiving contemporary risk-directed treatment protocols. Current efforts focus not only on further improving cure rate but also on patient quality of life. Hence, all protocols decrease or limit the use of cranial irradiation as central nervous system (CNS)-directed therapy, even in patients with high-risk presenting features, such as the presence of leukemia cells in the cerebrospinal fluid (even resulting from traumatic lumbar puncture), adverse genetic features, T-cell immunophenotype, and a large leukemia-cell burden. Current strategies for CNS-directed therapy involve effective systemic chemotherapy (eg, dexamethasone, high-dose methotrexate, intensive asparaginase, ifosfamide) and early intensification and optimization of intrathecal therapy. Options under investigation for the treatment of relapsed or refractory CNS leukemia in ALL patients include thiotepa and intrathecal liposomal cytarabine. CNS involvement in non-Hodgkin’s lymphoma (NHL) is associated with young age, advanced stage, number of extranodal sites, elevated lactate dehydrogenase, and International Prognostic Index score. Refractory CNS lymphoma in patients with NHL carries a poor prognosis, with a median survival of 2 to 6 months; the most promising treatment, autologous stem cell transplant, can extend median survival from 10 to 26 months. CNS prophylaxis is required during the initial treatment of NHL subtypes that carry a high risk of CNS relapse, such as B-cell ALL, Burkitt’s lymphoma, and lymphoblastic lymphoma. The use of CNS prophylaxis in the treatment of diffuse large B-cell lymphoma is controversial because of the low risk of CNS relapse (~5%) in this population. In this article, we review current and past practice of intrathecal therapy in ALL and NHL and the risk-models that aim to identify predictors of CNS relapse in NHL.
PMCID: PMC2805279  PMID: 19660680
acute lymphoblastic leukemia; CNS-directed therapy; liposomal cytarabine; thiotepa
2.  Challenging issues in pediatric oncology 
Improvements in protocol-driven clinical trials and supportive care for children and adolescents with cancer have reduced mortality rates by more than 50% over the past three decades. Overall, the 5-year survival rate for pediatric cancer patients has increased to approximately 80%. Recognition of the biological heterogeneity within specific subtypes of cancer, the discovery of genetic lesions that drive malignant transformation and cancer progression, and improved understanding of the basis of drug resistance will undoubtedly catalyze further advances in risk-directed treatments and the development of targeted therapies, boosting the cure rates further. Emerging new treatments include novel formulations of existing chemotherapeutic agents, monoclonal antibodies against cancer-associated antigens, and molecular therapies that target genetic lesions and their associated signaling pathways. Recent findings that link pharmacogenomic variations with drug exposure, adverse effects, and efficacy should accelerate efforts to develop personalized therapy for individual patients. Finally, palliative care should be included as an essential part of cancer management to prevent and relieve the suffering and to improve the quality of life of patients and their families.
PMCID: PMC3234106  PMID: 21709698
3.  Biology, Risk Stratification, and Therapy of Pediatric Acute Leukemias: An Update 
Journal of Clinical Oncology  2010;29(5):551-565.
We review recent advances in the biologic understanding and treatment of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), identify therapeutically challenging subgroups, and suggest future directions of research.
A review of English literature on childhood acute leukemias from the past 5 years was performed.
Contemporary treatments have resulted in 5-year event-free survival rates of approximately 80% for childhood ALL and almost 60% for pediatric AML. The advent of high-resolution genome-wide analyses has provided new insights into leukemogenesis and identified many novel subtypes of leukemia. Virtually all ALL and the vast majority of AML cases can be classified according to specific genetic abnormalities. Cooperative mutations involved in cell differentiation, cell cycle regulation, tumor suppression, drug responsiveness, and apoptosis have also been identified in many cases. The development of new formulations of existing drugs, molecularly targeted therapy, and immunotherapies promises to further advance the cure rates and improve quality of life of patients.
The application of new high-throughput sequencing techniques to define the complete DNA sequence of leukemia and host normal cells and the development of new agents targeted to leukemogenic pathways promise to further improve outcome in the coming decade.
PMCID: PMC3071256  PMID: 21220611
4.  Intrathecal liposomal cytarabine: More friend than foe? 
Leukemia & lymphoma  2008;49(8):1427-1430.
PMCID: PMC2803076  PMID: 18766957
5.  Acute Lymphoblastic Leukemia: Introduction 
Seminars in hematology  2009;46(1):1-2.
PMCID: PMC2638983  PMID: 19100362
6.  Systematic Review and Meta-analysis of Randomized Trials of Central Nervous System Directed Therapy for Childhood Acute Lymphoblastic Leukaemia 
Pediatric blood & cancer  2012;60(2):185-195.
Treatment of the central nervous system (CNS) is an essential therapy component for childhood acute lymphoblastic leukaemia (ALL). Individual patient data from 47 trials addressing 16 CNS treatment comparisons were analyzed. Event-free survival (EFS) was similar for radiotherapy versus IT, and radiotherapy plus IT versus IVMTX plus IT. Triple intrathecal therapy (TIT) gave similar EFS but poorer survival than ITMTX, but additional IVMTX improved both outcomes. One trial resulted in similar EFS and survival with IVMTX plus ITMTX versus TIT alone. Radiotherapy can generally be replaced by IT therapy. TIT should be used with effective systemic therapy such as IVMTX.
PMCID: PMC3461084  PMID: 22693038
Leukaemia; Meta-analysis; childhood leukaemia; CNS; triple intrathecal therapy
7.  A Healthcare System Perspective on Implementing Genomic Medicine: Pediatric Acute Lymphoblastic Leukemia as a Paradigm 
The promise of genomic medicine has received great attention over the past decade, projecting how genomics will soon guide the prevention, diagnosis, and treatment of human diseases. However, this evolution has been slower than forecast, even where evidence is often strong (e.g., pharmacogenomics). Reasons include the requirement for institutional resources and the need for the will to push beyond barriers impeding health-care changes. Here, we illustrate how genomics has been deployed to advance the treatment of childhood leukemia.
PMCID: PMC3720796  PMID: 23462885
pharmacogenomics; genetic testing; personalized medicine; cancers; pharmacokinetics
8.  Prospective Randomized Crossover Evaluation of Three Anesthetic Regimens for Painful Procedures in Children with Cancer 
The Journal of pediatrics  2012;162(1):137-141.
To identify the most effective sedation regimen for bone marrow aspiration and lumbar puncture procedures with a prospective trial of 3 combinations of sedation/analgesia.
Study design
In this double-blind crossover study, we randomly assigned 162 children with acute lymphoblastic leukemia or lymphoblastic lymphoma to receive fentanyl 1 mcg/kg, fentanyl 0.5 mcg/kg, or placebo, in addition to propofol and topical anesthetic for 355 procedures.
We found no significant differences among the three regimens in the frequency of pain (pain score >0) or severe pain (PS ≥5) during recovery, or a >20% increase in hemodynamic/respiratory variables during anesthesia. Treatment with fentanyl 1 mcg/kg was associated with a lower frequency of movement during procedure as compared with treatment with fentanyl 0.5mcg/kg (P = 0.0476) or treatment with placebo (P = 0.0545). The placebo group required longer time to recover (median, 18 minutes) as compared with the fentanyl 0.5 mcg/kg group (median, 9 minutes) (median difference 2.0, P = 0.007) and the fentanyl 1 mcg/kg (median 8 minutes), (median difference 2.0, P = 0.15). The placebo group also required larger total dose of propofol (median 5 mg/kg) as compared with that of the fentanyl 1 mcg/kg group (median, 3.5 mg/kg) and the fentanyl 0.5 mcg/kg group (median 3.5 mg/kg) (median differences 1.5, P <0.00005, in both comparisons).
The addition of fentanyl 1 mcg/kg to propofol for brief painful procedures reduces movement, propofol dose, and recovery time.
PMCID: PMC3529769  PMID: 22883421
pain; sedation; procedures; bone marrow aspiration; pediatric oncology
9.  Treatment Outcome in Older Patients with Childhood Acute Myeloid Leukemia 
Cancer  2012;118(24):6253-6259.
Older age has historically been an adverse prognostic factor in pediatric acute myeloid leukemia (AML). 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 three 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 10- to 21-year-old patients compared to 2 earlier studies (AML91 and 97), with 3-year rates of event-free survival (EFS), overall survival (OS) and cumulative incidence of refractory leukemia or relapse (CIR) for this group similar to those of 0- to 9-year old patients: EFS, 58.3% ± 5.4% vs. 66.6% ± 4.9%, P=.20; OS, 68.9% ± 5.1% vs. 75.1% ± 4.5%, P=.36; cumulative incidence of refractory leukemia or relapse, 21.9% ± 4.4%; vs. 25.3% ± 4.1%, P=.59. EFS and OS estimates for 10–15-year-old patients overlapped those for 16–21-year-old patients. However, the cumulative incidence of toxic death was significantly higher for 10- to 21-year-old patients compared to younger patients (13.2% ± 3.6 vs. 4.5% ± 2.0%, P=.028).
The survival rate for older children with AML has improved on our recent trial and is now similar to that of younger patients. However, deaths from toxicity remain a significant problem in the older age group. Future trials should focus on improving supportive care while striving to develop more effective antileukemic therapy.
PMCID: PMC3557958  PMID: 22674050
acute myeloid leukemia; age; pediatrics; adolescents; prognosis
10.  Effect of Body Mass Index on the Outcome of Children with Acute Myeloid Leukemia 
Cancer  2012;118(23):5989-5996.
The effect of body mass index (BMI) on treatment outcome of children with acute myeloid leukemia (AML) is unclear and needs further evaluation.
Children with AML (n=314) 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 (8.0%) patients were underweight, 86 (27.4%) overweight/obese, and 203 (64.6%) had healthy weight. Five-year overall survival of overweight/obese patients (46.5±7.3%) was lower than that 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 adjusting for age, leukocyte count, FAB type, 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 but underweight and overweight/obese patients had a significantly higher cumulative incidence of treatment-related mortality, especially due to infection (P = .009).
An unhealthy BMI is 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.
PMCID: PMC3434283  PMID: 22648558
body mass index; children; acute myeloid leukemia; survival; toxicity
11.  Longitudinal Changes in Body Mass and Composition in Survivors of Childhood Hematologic Malignancies After Allogeneic Hematopoietic Stem-Cell Transplantation 
Journal of Clinical Oncology  2012;30(32):3991-3997.
To measure longitudinal changes in body mass and composition in survivors of childhood hematologic malignancies after allogeneic hematopoietic stem-cell transplantation (HSCT).
Patients and Methods
Body mass index (BMI) was analyzed in 179 survivors by category (underweight, healthy-weight, overweight, and obese) and by z score. Fat and lean body mass measured by dual-energy x-ray absorptiometry was analyzed as z scores.
Over a median 6.6 years of follow-up, BMI z scores diminished significantly (0.32 pre-HSCT v −0.60 at 10 years post-HSCT; P < .001). Mean z scores for fat mass stayed within population norms, but those for lean mass remained below normal levels and diminished significantly over time (P = .018). Pre-HSCT BMI category and/or z score were strongly predictive of post-HSCT BMI (P < .001) and of fat and lean mass z scores (both P < .001). Survivors with extensive chronic graft-versus-host disease were more likely than others to have low BMI (P = .004) and low lean mass (P < .001) post-HSCT. Older age at HSCT (P = .015) and T-cell–depleted graft (P = .018) were predictive of lower post-HSCT BMI. Female patients had higher body fat (P = .002) and lower lean mass (P = .013) z scores than male patients, and black patients had higher fat mass z scores than white patients (P = .026).
BMI declines significantly after allogeneic HSCT for childhood hematologic malignancies, reflecting primarily a substantial decrease in lean mass but not fat mass. Monitoring and preservation of BMI and lean mass are vital, especially in those with the identified risk factors.
PMCID: PMC3675688  PMID: 23032628
12.  PACSIN2 polymorphism influences TPMT activity and mercaptopurine-related gastrointestinal toxicity 
Human Molecular Genetics  2012;21(21):4793-4804.
Treatment-related toxicity can be life-threatening and is the primary cause of interruption or discontinuation of chemotherapy for acute lymphoblastic leukemia (ALL), leading to an increased risk of relapse. Mercaptopurine is an essential component of continuation therapy in all ALL treatment protocols worldwide. Genetic polymorphisms in thiopurine S-methyltransferase (TPMT) are known to have a marked effect on mercaptopurine metabolism and toxicity; however, some patients with wild-type TPMT develop toxicity during mercaptopurine treatment for reasons that are not well understood. To identify additional genetic determinants of mercaptopurine toxicity, a genome-wide analysis was performed in a panel of human HapMap cell lines to identify trans-acting genes whose expression and/or single-nucleotide polymorphisms (SNPs) are related to TPMT activity, then validated in patients with ALL. The highest ranking gene with both mRNA expression and SNPs associated with TPMT activity in HapMap cell lines was protein kinase C and casein kinase substrate in neurons 2 (PACSIN2). The association of a PACSIN2 SNP (rs2413739) with TPMT activity was confirmed in patients and knock-down of PACSIN2 mRNA in human leukemia cells (NALM6) resulted in significantly lower TPMT activity. Moreover, this PACSIN2 SNP was significantly associated with the incidence of severe gastrointestinal (GI) toxicity during consolidation therapy containing mercaptopurine, and remained significant in a multivariate analysis including TPMT and SLCO1B1 as covariates, consistent with its influence on TPMT activity. The association with GI toxicity was also validated in a separate cohort of pediatric patients with ALL. These data indicate that polymorphism in PACSIN2 significantly modulates TPMT activity and influences the risk of GI toxicity associated with mercaptopurine therapy.
PMCID: PMC3471396  PMID: 22846425
13.  Comparative Analysis of Different Approaches to Measure Treatment Response in Acute Myeloid Leukemia 
Journal of Clinical Oncology  2012;30(29):3625-3632.
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.
Patients and Methods
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 CBFβ-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 CBFβ-MYH11 transcripts is largely uninformative.
PMCID: PMC3462046  PMID: 22965955
14.  Between-course targeting of methotrexate exposure using pharmacokinetically guided dosage adjustments 
It is advantageous to individualize high-dose methotrexate (HDMTX) to maintain adequate exposure while minimizing toxicities. Previously, we accomplished this through within-course dose adjustments.
In this study, we evaluated a strategy to individualize HDMTX based on clearance of each individual’s previous course of HDMTX in 485 patients with newly diagnosed acute lymphoblastic leukemia. Doses were individualized to achieve a steady-state plasma concentration (Cpss) of 33 or 65 μM (approximately 2.5 or 5 g/m2/day) for low- and standard-/high-risk patients, respectively.
Individualized doses resulted in 70 and 63 % of courses being within 20 % of the targeted Cpss in the low- and standard-/high-risk arms, respectively, compared to 60 % (p < 0.001) and 61 % (p = 0.43) with conventionally dosed therapy. Only 1.3 % of the individualized courses in the standard-/high-risk arm had a Cpss greater than 50 % above the target compared to 7.3 % (p < 0.001) in conventionally dosed therapy. We observed a low rate (8.5 % of courses) of grade 3–4 toxicities. The odds of gastrointestinal toxicity were related to methotrexate plasma concentrations in both the low (p = 0.021)- and standard-/high-risk groups (p = 0.003).
Individualizing HDMTX based on the clearance from the prior course resulted in fewer extreme Cpss values and less delayed excretion compared to conventional dosing.
Electronic supplementary material
The online version of this article (doi:10.1007/s00280-013-2206-x) contains supplementary material, which is available to authorized users.
PMCID: PMC3719000  PMID: 23760811
Methotrexate; Acute lymphoblastic leukemia; Pharmacokinetics; Individualized therapy
15.  Treatment Outcomes in Black and White Children With Cancer: Results From the SEER Database and St Jude Children's Research Hospital, 1992 Through 2007 
Journal of Clinical Oncology  2012;30(16):2005-2012.
Treatment outcome for black patients with cancer has been significantly worse than for their white counterparts. We determined whether recent improved treatment had narrowed the gap in outcome between black and white pediatric patients.
Patients and Methods
In a parallel comparison, we analyzed survival by disease category between black and white patients with childhood cancer registered in one of the 17 cancer registries of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program or treated at St Jude Children's Research Hospital, which provides comprehensive treatment to all patients regardless of their ability to pay, from 1992 to 2000 and from 2001 to 2007.
Analysis of the SEER data indicated that in both study periods, black patients had significantly poorer rates of survival than did white patients, with the exception of a few types of cancer. Despite significantly improved treatment outcomes for patients who were treated from 2001 to 2007, the racial difference in survival has actually widened for acute myeloid leukemia and neuroblastoma. By contrast, in the cohorts treated at St Jude Children's Research Hospital, there were no significant differences in survival between black and white patients in either study period, regardless of the cancer type. Importantly, the outcome of treatment for acute lymphoblastic leukemia, acute myeloid leukemia, and retinoblastoma has improved in parallel for both races during the most recent study period.
With equal access to comprehensive treatment, black and white children with cancer can achieve the same high cure rates.
PMCID: PMC3383176  PMID: 22547602
16.  The Pediatric Cancer Genome Project 
Nature genetics  2012;44(6):619-622.
The St. Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project (PCGP) is participating in the international effort to identify somatic mutations that drive cancer. These cancer genome sequencing efforts will not only yield an unparalleled view of the altered signaling pathways in cancer but should also identify new targets against which novel therapeutics can be developed. Although these projects are still deep in the phase of generating primary DNA sequence data, important results are emerging and valuable community resources are being generated that should catalyze future cancer research. We describe here the rationale for conducting the PCGP, present some of the early results of this project and discuss the major lessons learned and how these will affect the application of genomic sequencing in the clinic.
PMCID: PMC3619412  PMID: 22641210
17.  Pharmacogenomics and individualized medicine: Translating science into practice 
Research on genes and medications has advanced our understanding of the genetic basis of individual drug responses. The aim of pharmacogenomics is to develop strategies for individualizing therapy for patients, to optimize outcome through knowledge of human genome variability and its influence on drug response. Pharmacogenomics research is translational in nature and ranges from discovery of genotype-phenotype relationships to clinical trials which provide proof of clinical impact. Advances in pharmacogenomics offer significant potential for subsequent clinical application in individual patients; however, the translation of pharmacogenomics research findings into clinical practice has been slow. Key components to successful clinical implementation of pharmacogenomics will include consistent interpretation of pharmacogenomic test results, availability of clinical guidelines for prescribing based on test results, and knowledge-based decision support systems.
PMCID: PMC3589526  PMID: 22948889
pharmacogenomics; genetic testing; personalized medicine
18.  Second Malignant Neoplasms and Cardiovascular Disease Following Radiotherapy 
Second malignant neoplasms (SMNs) and cardiovascular disease (CVD) are among the most serious and life-threatening late adverse effects experienced by the growing number of cancer survivors worldwide and are due in part to radiotherapy. The National Council on Radiation Protection and Measurements (NCRP) convened an expert scientific committee to critically and comprehensively review associations between radiotherapy and SMNs and CVD, taking into account radiobiology; genomics; treatment (ie, radiotherapy with or without chemotherapy and other therapies); type of radiation; and quantitative considerations (ie, dose–response relationships). Major conclusions of the NCRP include: 1) the relevance of older technologies for current risk assessment when organ-specific absorbed dose and the appropriate relative biological effectiveness are taken into account and 2) the identification of critical research needs with regard to newer radiation modalities, dose–response relationships, and genetic susceptibility. Recommendation for research priorities and infrastructural requirements include 1) long-term large-scale follow-up of extant cancer survivors and prospectively treated patients to characterize risks of SMNs and CVD in terms of radiation dose and type; 2) biological sample collection to integrate epidemiological studies with molecular and genetic evaluations; 3) investigation of interactions between radiotherapy and other potential confounding factors, such as age, sex, race, tobacco and alcohol use, dietary intake, energy balance, and other cofactors, as well as genetic susceptibility; 4) focusing on adolescent and young adult cancer survivors, given the sparse research in this population; and 5) construction of comprehensive risk prediction models for SMNs and CVD to permit the development of follow-up guidelines and prevention and intervention strategies.
PMCID: PMC3295744  PMID: 22312134
19.  Nutritional Intake of Long Term Survivors of Childhood Acute Lymphoblastic Leukemia: Evidence for Bone Health Interventional Opportunities 
Pediatric blood & cancer  2010;55(7):1362-1369.
Survivors of childhood acute lymphoblastic leukemia (ALL) are vulnerable to exaggeration of the aging process including decreased bone mineral density (BMD). As little is known about their dietary or nutrient intake that may affect their long-term bone health, we examined nutrient intake in long-term survivors of childhood ALL.
Survivors (n=164) of childhood ALL who had completed treatment for at least 5 years and were in continuous remission, completed a 110-item food questionnaire that reflected dietary intake over the previous year. The analyzed cohort comprised 34 females and 38 males younger than 19 years and 45 females and 47 males at least 19 years. Reported nutrient intake and food selection were compared with age-specific Recommended Dietary Allowance and USDA Pyramid Food Guide. Body mass index was compared to the general US population, adjusted for age, gender, Tanner stage and race.
Less than 30% of participants met recommended dietary intakes for vitamin D, calcium, potassium or magnesium regardless of age. Mean daily caloric intake was 2204 Kcal (51% from carbohydrates) for younger and 2160 Kcal (49% from carbohydrates) for older participants. Energy intake from sweets was 70% higher than recommended. Participants <19 years were less likely to have a healthy weight (Odds Ratio.0.48, 95% CI 0.30-0.79); < 19 years more likely to be overweight (Odds Ratio 1.95, 95% CI 1.11-3.32, p<0.002)
Survivors of childhood ALL need careful dietary intervention to optimize long-term health.
PMCID: PMC3586793  PMID: 20981691
body mass index; dietary intake; acute lymphoblastic leukemia; pediatric leukemia; childhood cancer survivors
20.  Healthcare-Associated Infections at a Children's Cancer Hospital, 1983–2008 
Little is known about the incidence and etiology of healthcare-associated infections in immunosuppressed children.
Data collected prospectively between 1983 and 2008 were used to analyze changes in the rate, types of infection, and infecting organisms over time in patients treated at a children's cancer hospital. Neutropenia was evaluated as a risk factor.
Over the 26-year study period, 1986 healthcare-associated infections were identified during 1653 hospitalizations. The infection rate decreased significantly from 5.6 to 2.0 infections per 100 discharges (P < .01) and from 9.0 to 3.7 infections per 1000 patient-days (P < .01). Bloodstream infections were the most common type of infection (32.7% of all infections). Staphylococci (46.4% of Gram-positive bacteria), Escherichia coli (36.7% of Gram-negative bacteria), and Candida spp. (68.7% of fungi) were the most common pathogens isolated. An absolute neutrophil count (ANC) nadir <100 per mm3 was significantly associated (P < .0001) with an increased rate of infections compared with higher ANC nadirs.
Despite a steady expansion in hospital capacity and patient encounters over the last 3 decades, rates of healthcare-associated infections decreased significantly at our hospital. These data suggest that sustained decreases in the rate of healthcare-associated infections in immunosuppressed children are possible. An ANC <100 per mm3 is a risk factor for healthcare-associated infections in this population.
PMCID: PMC3656547  PMID: 23687571
21.  Proximal Tubular Secretion of Creatinine by Organic Cation Transporter OCT2 in Cancer Patients 
Clinical Cancer Research  2012;18(4):1101-1108.
Knowledge of transporters responsible for the renal secretion of creatinine is key to a proper interpretation of serum creatinine and/or creatinine clearance as markers of renal function in cancer patients receiving chemotherapeutic agents.
Experimental Design
Creatinine transport was studied in transfected HEK293 cells in vitro and in wildtype mice and age-matched organic cation transporter 1 and 2-deficient [Oct1/2(−/−)] mice ex vivo and in vivo. Clinical pharmacogenetic and transport inhibition studies were done in two separate cohorts of cancer patients.
Compared to wildtype mice, creatinine clearance was significantly impaired in Oct1/2(−/−) mice. Furthermore, creatinine inhibited organic cation transport in freshly-isolated proximal tubules from wild-type mice and humans, but not in those from Oct1/2(−/−) mice. In a genetic-association analysis (n=590), several polymorphisms around the OCT2/SLC22A2 gene locus, including rs2504954 (P=0.000873), were significantly associated with age-adjusted creatinine levels. Furthermore, in cancer patients (n=68), the OCT2 substrate cisplatin caused an acute elevation of serum creatinine (P=0.0083), consistent with inhibition of an elimination pathway.
Collectively, this study shows that OCT2 plays a decisive role in the renal secretion of creatinine. This process can be inhibited by OCT2 substrates, which impair the usefulness of creatinine as a marker of renal function.
PMCID: PMC3288323  PMID: 22223530
OCT2; Creatinine; Cisplatin
22.  Neuromuscular impairments in adult survivors of childhood acute lymphoblastic leukemia: associations with physical performance and chemotherapy doses 
Cancer  2011;118(3):828-838.
Treatment regimens for childhood acute lymphoblastic leukemia (ALL) contain neurotoxic agents that may interfere with neuromuscular health. This study examined associations between neuromuscular impairments and physical function, and between neuromuscular impairments, and doses of vincristine and intrathecal methotrexate used to treat leukemia among survivors of childhood ALL.
ALL survivors 10+ years from diagnosis participated in neuromuscular performance testing. Treatment data were abstracted from medical records. Regression models were used to evaluate associations between treatment factors, neuromuscular impairments and physical performance.
Among 415 survivors (median age 35 years; range 21–52), balance, mobility and six-minute walk (6MW) distances were 1.3 standard deviations below age- and sex-specific values in 15.4%, 3.6% and 46.5% of participants, respectively. Impairments included absent Achilles tendon reflexes (39.5%), active dorsiflexion range of motion (ROM) < 5 degrees (33.5%) and impaired knee extension strength (30.1%). In adjusted models (including cranial radiation), survivors treated with intrathecal methotrexate cumulative doses 215+ mg/m2 were 3.4 (95% CI 1.2–9.8) times more likely than survivors who received no intrathecal methotrexate, and those who received vincristine cumulative doses 39+ mg/m2 1.5 (95% CI 1.0–2.5) times more likely than those who received lower doses to have impaired ROM. Higher intrathecal methotrexate doses were associated with reduced knee extension strength and 6MW distances.
Neuromuscular impairments are prevalent in childhood ALL survivors and interfere with physical performance. Higher cumulative doses of vincristine and/or intrathecal methotrexate are associated with long-term neuromuscular impairments, which have implications on future function as these survivors age.
PMCID: PMC3197897  PMID: 21766297
Acute Lymphoblastic Leukemia; Survivor; Neuromuscular impairment; Function; Physical performance; Intrathecal methotrexate; Vincristine; Late effect
23.  The Controversy of Varicella Vaccination in Children with Acute Lymphoblastic Leukemia 
Pediatric blood & cancer  2010;58(1):12-16.
The available guidelines for varicella vaccination of susceptible children with acute lymphoblastic leukemia (ALL) have become increasingly conservative. However, vaccination of those who have remained in continuous complete remission for one year and are receiving chemotherapy is still considered a reasonable option. There is little available data to allow a comparison of the risk vs. benefit of vaccinating these patients.
We retrospectively reviewed mortality due to varicella in the records of 15 pediatric ALL study groups throughout Europe, Asia, and North America during the period 1984–2008.
We found that 20 of 35,128 children with ALL (0.057%; 95% confidence interval [CI], 0.037%–0.088%) died of VZV infection. The mortality rate was lower in North America (3 of 11,558 children, 0.026%; 95% CI, 0.009%–0.076%) than in the Asian countries (2 of 4,882 children, 0.041%; 95% CI, 0.011%–0.149%) and in Europe (15 of 18,688 children, 0.080%; 95% CI, 0.049%–0.132%) consistent with the generally higher rate of VZV vaccination in North America. Fourteen of the 20 patients (70%) died during the first year of treatment for ALL. One death was attributed to varicella vaccination.
The negligible rate of fatal varicella infection in children with ALL, the risk that accompanies vaccination, and the necessity of withholding chemotherapy for vaccination appear to outweigh the potential benefit of varicella vaccination for children during treatment of ALL.
PMCID: PMC3004985  PMID: 20848637
varicella zoster virus; pediatric; acute lymphoblastic leukemia; vaccination; immunization; mortality
25.  Longitudinal analysis of antibody response to immunization in paediatric survivors after allogeneic haematopoietic stem cell transplantation 
British journal of haematology  2011;156(1):109-117.
The long-term antibody responses to re-immunization in recipients of allogeneic haematopoietic stem cell transplantation (allo-HSCT) have not been well studied. We prospectively and longitudinally evaluated the antibody responses to 8 vaccine antigens (diphtheria, tetanus, pertussis, measles, mumps, rubella, hepatitis B, and poliovirus) and assessed the factors associated with negative titres in 210 allo-HSCT recipients at St. Jude Children’s Research Hospital. Antibody responses lasting for more than 5 years after immunization were observed in most patients for tetanus (95.7%), rubella (92.3%), poliovirus (97.9%), and, in diphtheria-tetanus-acellular pertussis (DTaP) recipients, diphtheria (100%). However, responses to pertussis (25.0%), measles (66.7%), mumps (61.5%), hepatitis B (72.9%), and diphtheria in tetanus-diphtheria (Td) recipients (48.6%) were less favourable, with either only transient antibody responses or persistently negative titres. Factors associated with vaccine failure were older age at immunization; lower CD3, CD4 or CD19 counts; higher IgM concentrations; positive recipient cytomegalovirus serology; negative titres before immunization; acute or chronic graft-versus-host disease; and radiation during preconditioning. These response patterns and clinical factors can be used to formulate re-immunization and monitoring strategies. Patients at risk for vaccine failure should have long-term follow-up; those with loss of antibody response or no seroconversion should receive booster immunizations.
PMCID: PMC3237834  PMID: 22017512
childhood; haematopoietic stem cell transplantation; allogeneic; immunization; survivor

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