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1.  Pediatric Oncology as the Next Global Child Health Priority: The Need for National Childhood Cancer Strategies in Low- and Middle-Income Countries 
PLoS Medicine  2014;11(6):e1001656.
Dr. Sumit Gupta and colleagues discuss the need for national cancer strategies for children in low- and middle-income countries and suggest how such strategies could be implemented.
Please see later in the article for the Editors' Summary
PMCID: PMC4061014  PMID: 24936984
2.  Prognostic Impact of Absolute Lymphocyte Counts at the End of Remission Induction in Childhood Acute Lymphoblastic Leukemia 
Cancer  2013;119(11):10.1002/cncr.28026.
Absolute lymphocyte counts (ALC) during treatment have been associated with outcome in children and adults with hematologic malignancies. However, the impact of ALC relative to that of other prognostic factors on the outcome of children with acute lymphoblastic leukemia (ALL) treated in recent trials is unknown.
Outcomes of 399 patients ≤ 18 years of age with newly diagnosed ALL who were enrolled in the Total Therapy XV study at St. Jude Children’s Research Hospital were analyzed according to ALC at the end of remission induction therapy.
ALC ≥ 500 cell/μL was significantly more prevalent among patients with B-lineage ALL, favorable presenting features and in those who achieved minimal residual disease (MRD) negativity on day 43 of treatment. Both overall survival (OS) and event-free survival (EFS) were superior among patients with higher ALC, but only the association with OS was statistically significant in a univariate analysis. In multivariable analyses, ALC was not a significant predictor of outcome after controlling for age, leukocyte count, lineage, risk group, and MRD at the end of induction (p > 0.1 for all comparisons). However, among MRD-negative patients, those with low ALC had a 5-year OS of 84.2% ± 8.9% versus 97.3 ± 1.0 for patients with higher ALC (P = .036).
ALC at the end of induction is related to favorable presenting features and good initial treatment response but does not independently predict outcome in the context of contemporary, MRD-guided, therapy.
PMCID: PMC3862024  PMID: 23456849
acute lymphoblastic leukemia; lymphocytes; pediatrics; prognosis
3.  Management of children with brain tumors in Paraguay 
Neuro-Oncology  2012;15(2):235-241.
Cure rates among children with brain tumors differ between low-income and high-income countries. To evaluate causes of these differences, we analyzed aspects of care provided to pediatric neuro-oncology patients in a low middle-income South American country.
Three methods were used to evaluate treatment of children with brain tumors in Paraguay: (1) a quantitative needs assessment questionnaire for local treating physicians, (2) site visits to assess 3 tertiary care centers in Asunción and a satellite clinic in an underdeveloped area, and (3) interviews with health care workers from relevant disciplines to determine their perceptions of available resources. Treatment failure was defined as abandonment of therapy, relapse, or death.
All 3 tertiary care facilities have access to chemotherapy and pediatric oncologists but lack training and tools for neuropathology and optimal neurosurgery. The 2 public hospitals also lack access to appropriate radiological tests and timely radiotherapy. These results demonstrate disparities in Paraguay, with rates of treatment failure ranging from 37% to 83% among the 3 facilities.
National and center-specific deficiencies in resources to manage pediatric brain tumors contribute to poor outcomes in Paraguay and suggest that both national and center-specific interventions are warranted to improve care. Disparities in Paraguay reflect different levels of governmental and philanthropic support, program development, and socio-economic status of patients and families, which must be considered when developing targeted strategies to improve management. Effective targeted interventions can serve as a model to develop pediatric brain tumor programs in other low- and middle-income countries.
PMCID: PMC3548583  PMID: 23197688
brain tumors; children; low-income country; Paraguay
4.  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
5.  Resumption of High-dose Methotrexate after Acute Kidney Injury and Glucarpidase Use in Pediatric Oncology Patients 
Cancer  2012;118(17):4321-4330.
High-dose methotrexate (HDMTX)-induced acute kidney injury is a rare but life-threatening complication. The methotrexate rescue agent glucarpidase rapidly hydrolyzes methotrexate to inactive metabolites. We retrospectively reviewed glucarpidase use in pediatric cancer patients at our institution and evaluated whether subsequent resumption of HDMTX was tolerated.
Clinical data and outcomes of all patients who received glucarpidase after HDMTX administration were reviewed.
Of 1,141 patients treated with 4,909 courses of HDMTX, 20 patients (1.8% of patients, 0.4% of courses) received 22 doses of glucarpidase. The median glucarpidase dosage was 51.6 units/kg (range, 13 – 65.6 units/kg). At the time of administration, the median plasma methotrexate concentration was 29.1 µM (range, 1.3 – 590.6 µM). Thirteen of the 20 patients received a total of 39 courses of HDMTX therapy after glucarpidase. The median time to complete methotrexate excretion was 355 hours (range, 244 – 763 hours) for the HDMTX course during which glucarpidase was administered, 90 hours (range, 66 – 268 hours) for the next HDMTX course, and 72 hours (range, 42 – 116 hours) for subsequent courses. The median peak serum creatinine during these HDMTX courses was 2.2 mg/dL (range, 0.8 – 9.6 mg/dL), 0.8 mg/dL (range, 0.4 – 1.6 mg/dL), and 0.6 mg/dL (range, 0.4 – 0.9 mg/dL), respectively. One patient experienced nephrotoxicity upon rechallenge with HDMTX. Renal function eventually returned to baseline in all patients and no patient died as a result of methotrexate toxicity.
It is possible to safely resume HDMTX therapy after glucarpidase treatment for HDMTX-induced acute kidney injury.
PMCID: PMC3713608  PMID: 22252903
Carboxypeptidases; gamma-Glutamyl hydrolase; methotrexate/administration and dosage; methotrexate/adverse effects; compassionate use trials; renal insufficiency/chemically induced; pediatric
6.  Development and use of active clinical decision support for preemptive pharmacogenomics 
Active clinical decision support (CDS) delivered through an electronic health record (EHR) facilitates gene-based drug prescribing and other applications of genomics to patient care.
We describe the development, implementation, and evaluation of active CDS for multiple pharmacogenetic test results reported preemptively.
Materials and methods
Clinical pharmacogenetic test results accompanied by clinical interpretations are placed into the patient's EHR, typically before a relevant drug is prescribed. Problem list entries created for high-risk phenotypes provide an unambiguous trigger for delivery of post-test alerts to clinicians when high-risk drugs are prescribed. In addition, pre-test alerts are issued if a very-high risk medication is prescribed (eg, a thiopurine), prior to the appropriate pharmacogenetic test result being entered into the EHR. Our CDS can be readily modified to incorporate new genes or high-risk drugs as they emerge.
Through November 2012, 35 customized pharmacogenetic rules have been implemented, including rules for TPMT with azathioprine, thioguanine, and mercaptopurine, and for CYP2D6 with codeine, tramadol, amitriptyline, fluoxetine, and paroxetine. Between May 2011 and November 2012, the pre-test alerts were electronically issued 1106 times (76 for thiopurines and 1030 for drugs metabolized by CYP2D6), and the post-test alerts were issued 1552 times (1521 for TPMT and 31 for CYP2D6). Analysis of alert outcomes revealed that the interruptive CDS appropriately guided prescribing in 95% of patients for whom they were issued.
Our experience illustrates the feasibility of developing computational systems that provide clinicians with actionable alerts for gene-based drug prescribing at the point of care.
PMCID: PMC3957400  PMID: 23978487
pharmacogenetics; electronic health record; clinical decision support; personalized medicine
7.  Watchful waiting for some children with a mediastinal mass: the potential role for 18 F-fluorodeoxyglucose positron emission tomography: a case report and review of the literature 
BMC Pediatrics  2013;13:103.
Benign hyperplastic thymus is a rare but important differential diagnosis of anterior mediastinal lesions. Histological and radiological criteria are used to distinguish this benign condition from other malignant diseases but have their limitations, and biopsy of mediastinal masses can be risky. We report for the first time the diagnostic value of fluorodeoxyglucose 18 F positron emission tomography for patients with incidentally identified anterior mediastinal masses to avoid biopsy in some cases.
Case presentation
A 2 year old girl presented with new onset of emesis and constipation leading to the incidental discovery of an anterior mediastinal mass on radiograph. Chest computed tomography revealed cystic components within the mass concerning for a malignancy. Biopsy of the lesion and bone marrow aspiration and biopsy were negative but there was concern that the mediastinal biopsy may have missed the malignant component of the lesion. Hence, a positron emission tomography scan was obtained that showed mild homogeneous fluorodeoxyglucose 18 F avidity within the mass similar to that of normal thymus. The diagnosis of benign hyperplastic thymus was made.
The differential diagnosis of an incidentally found anterior mediastinal mass includes malignancy, but benign lesions such as benign hyperplastic thymus must also be considered, particularly when the complete blood count and biochemical profile are normal. Fluorodeoxyglucose 18 F positron emission tomography can help guide a clinician’s decision for further interventions and treatment.
PMCID: PMC3717068  PMID: 23841990
Mediastinal disease; Mediastinum; Positron-emission tomography; Thymus hyperplasia
8.  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
9.  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
10.  A Clinician-Driven Automated System for Integration of Pharmacogenetic Consults into an Electronic Medical Record 
PMCID: PMC3589522  PMID: 22990750
pharmacogenetics; electronic medical record; personalized medicine; cytochrome P450 2D6; thiopurine-methyltransferase
12.  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
Maintaining excellent cure rates in pediatric Hodgkin lymphoma while minimizing toxicity.
To evaluate the efficacy of 4 cycles of vinblastine, Adriamycin, methotrexate, and prednisone (VAMP) in patients with favorable risk Hodgkin lymphoma who achieve a complete response after 2 cycles and do not receive radiotherapy.
Design, Setting, and Patients
Multi-institutional, unblinded, non-randomized single group phase II clinical trial to assess the need for radiotherapy based on early response to chemotherapy. Eighty-eight eligible patients with Hodgkin lymphoma stage I and II (< 3 nodal sites, no B symptoms, mediastinal bulk, or extranodal extension) enrolled between March 3, 2000 through December 9, 2008. Data frozen March 12, 2012.
Patients who achieved a complete response (n=47) after 2 cycles received no radiotherapy, and those with less than complete response (n=41) were given 25.5 Gy involved field radiotherapy.
Main Outcome Measures
2-year event-free survival was the primary outcome measure. A 2-year event-free survival of greater than 90% was desired, and 80% was considered to be unacceptably low.
Two-year event-free survival was 90.8% (95% CI, 84.7% – 96.9%); for patients who did not require radiotherapy it was 89.4% (95% CI, 80.8% – 98%), compared with 92.5% (95% CI, 84.5% – 100%) for those who did (P=0.61). Most common acute side effects were neuropathic pain (2% of patients), nausea/vomiting (3% of patients), neutropenia (32% of cycles), and febrile neutropenia (2% of patients). Nine patients (10%) were hospitalized 11 times (3% of cycles) for febrile neutropenia or non-neutropenic infection. Long term side effects after radiotherapy were asymptomatic compensated hypothyroidism in 9 patients (10%), osteonecrosis and moderate osteopenia in 2 patients each, subclinical pulmonary dysfunction in 12 patients (26%) and asymptomatic left ventricular dysfunction in 4 patients (5%). No second malignant neoplasms were observed.
Among patients with favorable risk Hodgkin lymphoma and a complete early response to chemotherapy, the use of limited therapy resulted in a high rate of 2-year EFS.
PMCID: PMC3526806  PMID: 22735430
15.  Symptoms of Attention-Deficit/Hyperactivity Disorder in Long-Term Survivors of Childhood Leukemia 
Pediatric blood & cancer  2011;57(7):1191-1196.
Survivors of childhood acute lymphoblastic leukemia (ALL) sometimes have clinical features that suggest Attention-Deficit/Hyperactivity Disorder (ADHD), though few studies have examined specific symptoms in survivors.
Long-term survivors of childhood ALL (n=161) received a neurological examination, while parents completed rating scales to establish formal criteria for ADHD. Symptom profiles were generated and compared across demographic and treatment characteristics, as well as medical tests associated with brain pathology.
Prevalence rates of ADHD were similar in survivors (10.5%) compared to those reported in the general population (7–10%). However, 25.5% of survivors reported symptoms that impair functioning in multiple settings, with attention problems being most common. These symptoms were associated with cranial radiation therapy (CRT) (mean inattentive symptoms [SD] = 3.6 [3.19] for group treated with CRT vs. 1.6 [2.40] for non-CRT group, p=0.0006), and survivors who demonstrated impaired anti-saccades during the neurologic exam (mean inattentive symptoms [SD] = 3.4 [3.29] for those with impaired anti-saccades vs. 1.4 [2.41] for those with normal anti-saccades; p = 0.0004).
The presence of a neurologically-based phenotype of attention problems in survivors of leukemia that is not fully captured by the syndrome of ADHD suggests that treatments specific to childhood ALL should be explored.
PMCID: PMC3140624  PMID: 21280202
ALL; long-term survivor; Attention-Deficit/Hyperactivity Disorder
16.  Severe Thrombocytopenia with Iron Deficiency Anemia 
Pediatric hematology and oncology  2010;27(5):413-419.
Although severe thrombocytopenia has been reported among children with iron deficiency anemia, the presence of both anemia and thrombocytopenia can suggest serious or malignant bone marrow dysfunction, requiring further work-up. This paper reviews the management and outcomes of patients with the diagnosis of iron deficiency anemia presenting with severe thrombocytopenia.
We present four pediatric patients with iron deficiency anemia and severe thrombocytopenia at initial presentation. Charts were reviewed after approval by the institutional review boards at both St. Jude Children’s Research Hospital and LeBonheur Children’s Medical Center in Memphis, Tennessee.
Results and Conclusions
All four patient’s hemoglobin concentrations and platelet counts normalized within one to three weeks of initiating iron supplementation, suggesting that in such patients iron supplementation can obviate the need for invasive diagnostic procedures. In addition, these patients all had a platelet “overshoot” phenomenon during iron therapy prior to normalization of platelet counts, the mechanism of which is still unknown. The literature exploring the mechanism behind our clinical findings is reviewed.
PMCID: PMC3439835  PMID: 20670168
Anemia; iron deficiency; thrombocytopenia; children
17.  The Tumor Lysis Syndrome 
The New England journal of medicine  2011;364(19):1844-1854.
PMCID: PMC3437249  PMID: 21561350
18.  Improved Prognosis for Older Adolescents With Acute Lymphoblastic Leukemia 
Journal of Clinical Oncology  2010;29(4):386-391.
The prognosis for older adolescents and young adults with acute lymphoblastic leukemia (ALL) has been historically much worse than that for younger patients. We reviewed the outcome of older adolescents (age 15 to 18 years) treated in four consecutive Total Therapy studies to determine if recent improved treatment extended to this high-risk group.
Patients and Methods
Between 1991 and 2007, 963 pediatric patients, including 89 older adolescents, were enrolled on Total Therapy studies XIIIA, XIIIB, XIV, and XV. In the first three studies, treatment selection was based on presenting clinical features and leukemic cell genetics. In study XV, the level of residual disease was used to guide treatment, which featured intensive methotrexate, glucocorticoid, vincristine, and asparaginase, as well as early triple intrathecal therapy for higher-risk ALL.
The 89 older adolescents were significantly more likely to have T-cell ALL, the t(4;11)(MLL-AF4), and detectable minimal residual disease during or at the end of remission induction; they were less likely to have the t(12;21)(ETV6-RUNX1) compared with younger patients. In the first three studies, the 44 older adolescents had significantly poorer event-free survival and overall survival than the 403 younger patients. This gap in prognosis was abolished in study XV: event-free survival rates at 5 years were 86.4% ± 5.2% (standard error) for the 45 older adolescents and 87.4% ± 1.7% for the 453 younger patients; overall survival rates were 87.9% ± 5.1% versus 94.1% ± 1.2%, respectively.
Most older adolescents with ALL can be cured with risk-adjusted intensive chemotherapy without stem-cell transplantation.
PMCID: PMC3058285  PMID: 21172890
19.  Changes in Medical Care at a Pediatric Oncology Referral Center after Placement of a Do-Not-Resuscitate Order 
Journal of Palliative Medicine  2010;13(11):1349-1352.
Parents may fear that a do-not-resuscitate (DNR) order will result in reduction of the level, quality, and priority of their child's medical care. We therefore assessed medical care that was continued, added, and discontinued after a DNR order was placed in the medical record.
Retrospective review of the charts of 200 pediatric oncology patients at St. Jude Children's Research Hospital who died between July 1, 2001 and February 28, 2005, were younger than 22 years old at death, and had a documented DNR order. Medical interventions that were added (between the DNR order and death), continued (not discontinued between 24 hours before and 72 hours after DNR), and discontinued (within 72 hours after DNR) were identified and compared by using binomial proportions.
With the exception of chemotherapy, the studied medical interventions that patients were receiving at the time of the DNR order were continued in 66.7% to 99.3% of cases. Chemotherapy was continued in 33.3%. The most frequently added interventions were oxygen, steroids, and pain medicine. The most frequently discontinued interventions were laboratory draws, chemotherapy, antibiotics, and parenteral nutrition.
In this cohort of pediatric oncology patients, the medical interventions being received were continued with a high frequency after placement of a DNR order. Chemotherapy was continued only in a minority of patients, possibly signifying a shift in goals. These findings may help to reassure families that a DNR order need not result in a change in any of their child's medical therapies which appropriately advance the defined goals of care.
PMCID: PMC3001240  PMID: 21034279
20.  Long-Term Efficacy of Methylphenidate in Enhancing Attention Regulation, Social Skills, and Academic Abilities of Childhood Cancer Survivors 
Journal of Clinical Oncology  2010;28(29):4465-4472.
Methylphenidate (MPH) ameliorates attention problems experienced by some cancer survivors in the short term, but its long-term efficacy is unproven.
Patients and Methods
This study investigates the long-term effectiveness of maintenance doses of MPH in survivors of childhood brain tumors (n = 35) and acute lymphoblastic leukemia (n = 33) participating in a 12-month MPH trial. Measures of attention (Conners' Continuous Performance Test [CPT], Conners' Rating Scales [CRS]), academic abilities (Wechsler Individual Achievement Test [WIAT]), social skills (Social Skills Rating System [SSRS]), and behavioral problems (Child Behavior Checklist [CBCL]) were administered at premedication baseline and at the end of the MPH trial while on medication. A cancer control group composed of patients who were not administered MPH (brain tumor = 31 and acute lymphoblastic leukemia = 23) was assessed on the same measures 2 months apart.
For the MPH group, repeated measures analysis of variance revealed significant improvement in performance on a measure of sustained attention (CPT indices, P < .05); parent, teacher, and self-report ratings of attention (CRS indices, P < .05), and parent ratings of social skills or behavioral problems (SSRS and CBCL indices; P < .05). In contrast, the cancer control group only showed improvement on parent ratings of attention (Conners' Parent Rating Scale indices; P < .05) and social skills (SSRS and CBCL indices; P < .05). There was no significant improvement on the academic measure (WIAT) in either group.
Attention and behavioral benefits of MPH for childhood cancer survivors are maintained across settings over the course of a year. Although academic gains were not identified, MPH may offer benefits in academic areas not assessed.
PMCID: PMC2988638  PMID: 20837955
21.  Initial Response to Salvage Therapy Determines Prognosis in Relapsed Pediatric Hodgkin Lymphoma Patients 
Cancer  2010;116(18):4376-4384.
Pediatric Hodgkin lymphoma is a highly curable disease, however once a patient relapses prognostic factors for survival are not clearly defined.
Retrospective analysis of 50 pediatric patients with HL that relapsed or progressed between 1990 and 2006 and were retrieved with intense cytoreductive treatment regimens followed by autologous stem-cell transplantation and radiation therapy. A Cox proportional hazard model was used to determine risk factors for second treatment failure and death.
The median age was 16.1 years (range, 4.9 to 22.1 years) at diagnosis of HL. Fifteen patients developed progressive disease while on therapy, 14 relapsed early and 21 relapsed late. Patients who remained alive at the time of this study had been followed for a median of 4.4 years (range, 1.2 to 16.6 years). The 5-year overall survival of patients who had an inadequate response (n=14) to initial salvage therapy was only 17.9% (95% confidence interval [CI], 3.1% to 42.5%) compared with 97.2% (95% CI, 81.9% to 99.6%) for those who responded (n=36; P < 0.0001). In multiple variable Cox-regression analysis for overall survival, only inadequate response to initial salvage therapy was significant (hazard ratio, 43.6; 95% CI, 5.4 to 354; P = 0.0004).
Pediatric patients with relapsed HL who have an inadequate response after initial primary salvage chemotherapy have a very poor prognosis and should be considered for novel therapies directed at biological or immunological targets.
PMCID: PMC2936658  PMID: 20564743
Hodgkin lymphoma; treatment failure; pediatric; salvage therapy
22.  Effect of Allopurinol versus Urate Oxidase on Methotrexate Pharmacokinetics in Children with Newly Diagnosed Acute Lymphoblastic Leukemia 
Cancer  2010;116(1):227-232.
Allopurinol and urate oxidase are both effective in preventing or treating hyperuricemia during remission induction therapy for lymphoid malignancies, but their effect on concomitant anticancer drug therapy has not been compared.
We compared plasma methotrexate pharmacokinetics in pediatric patients with newly diagnosed acute lymphoblastic leukemia who received concomitant allopurinol (n=20) versus non-recombinant or recombinant urate oxidase (n=96) during high-dose methotrexate administration before conventional remission induction therapy.
The minimum plasma concentration of uric acid was significantly (p<0.0001) lower after treatment with urate oxidase as compared to allopurinol treatment. Methotrexate clearance was significantly higher (median, 117.1 vs. 91.1ml/min/m2, p=0.019) in patients receiving urate oxidase. A higher proportion of patients in the allopurinol group had elevated methotrexate plasma concentrations (36% vs. 7%, p=0.003), and experienced mucositis (45% vs. 16%, p=0.003) after methotrexate treatment than those in the rasburicase group.
The lower rate of methotrexate clearance in patients receiving allopurinol likely reflects a less potent hypouricemic effect of allopurinol, leading to precipitation of uric acid in renal tubules. Hence, during remission induction therapy for lymphoid malignancies, renally-excreted drugs should be monitored closely, especially in patients receiving allopurinol.
PMCID: PMC2846832  PMID: 19834958
methotrexate; acute lymphoblastic leukemia; hyperuricemia; allopurinol; urate oxidase
23.  Conservative Management of Pancreatic Pseudocysts in Children with Acute Lymphoblastic Leukemia 
Treatment with asparaginase for acute lymphoblastic leukemia (ALL) can cause acute pancreatitis. Complication of pancreatitis by pancreatic pseudocyst formation can prolong the hospital stay, delay chemotherapy, and necessitate long-term parenteral nutrition. We report five children with ALL who developed acute pancreatitis complicated by pancreatic pseudocysts. They required modifications to their chemotherapy regimen and prolonged parenteral nutrition but no surgical intervention. All five patients survive in first remission and their pseudocysts resolved after 3 to 37 months or continued to decrease in size at last follow-up. These cases illustrate that non-surgical management of pancreatic pseudocyst is safe, though pseudocyst resolution may require many months. In addition, these patients demonstrate that oral feeding can be initiated after the acute episode of pancreatitis resolves even if a pseudocyst is present.
PMCID: PMC2811578  PMID: 19956023
Pancreatitis; pancreatitis pseudocyst; L-asparaginase; pediatric oncology; acute lymphoblastic leukemia
24.  Increased Risk for CNS Relapse in Pre-B Cell Leukemia with the t(1;19)/TCF3-PBX1 
To evaluate the impact of contemporary therapy on the clinical outcome of children with pre-B acute lymphoblastic leukemia (ALL) and the t(1;19)/TCF3/PBX1, we analyzed 735 patients with B-cell precursor ALL treated in four successive protocols at St. Jude Children’s Research Hospital. The 41 patients with the t(1;19) had a comparable event-free survival to that of the 694 patients with other B-cell precursor ALL (p=0.63; 84.2% ± 7.1% [SE] vs. 84.0% ± 1.8% at 5 years). However, patients with the t(1;19) had a lower cumulative incidence of any hematological relapse (p=0.06; 0 vs. 8.3% ± 1.2% at 5 years) but a significantly higher incidence of central-nervous-system (CNS) relapse (p<0.001; 9.0% ± 5.1% vs. 1.0% ± 0.4% at 5 years). In a multivariate analysis, the t(1;19) was an independent risk factor for isolated CNS relapse. These data suggest that with contemporary treatment, patients with the t(1;19) and TCF3/PBX1 fusion have a favorable overall outcome but increased risk of CNS relapse.
PMCID: PMC2731684  PMID: 19282835
t(1;19); TCF3-PBX1; Pre-B ALL; Pediatric ALL; CNS relapse
25.  Side Effects of Methylphenidate in Survivors of Childhood Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial 
Pediatrics  2009;124(1):226-233.
To investigate the frequency and severity of side effects of methylphenidate (MPH) among childhood survivors of acute lymphoblastic leukemia (ALL) and brain tumors (BT), and to identify predictors of higher side effect levels.
Childhood cancer survivors (N = 103; BT=54, ALL=49) identified as having attention and learning problems completed a randomized, double-blind, three-week, home cross-over trial of placebo, low-dose MPH (LD; 0.3mg/kg; 10 mg maximum bid) and moderate-dose MPH (MD; 0.6 mg/kg; 20 mg maximum bid). Caregivers completed the Barkley Side Effects Rating Scale (SERS) at baseline and each week during the medication trial. Siblings of cancer survivors (N = 49) were recruited as a healthy comparison group.
There was a significantly higher number and severity of symptoms endorsed on the SERS when patients were taking MD compared to placebo or LD (ps <.001) but not LD compared to placebo (p =.143 and p =.635, respectively). The number of side effects endorsed on the SERS was significantly lower during all three home-cross over weeks (placebo, LD, MD) when compared to baseline symptom scores (ps <.001). The severity of side effects was also significantly lower, compared to baseline screening, during placebo and LD weeks (p <.001 and p =.003, respectively), but not MD week (p =.925). Both the number and severity of symptoms endorsed at baseline were significantly higher for patients compared to siblings (p <.001 and p =.004, respectively). Female gender and lower IQ were associated with higher side effect levels (ps <.05).
MPH is generally well tolerated by childhood cancer survivors. There is a subgroup at increased risk for side effects that may need to be closely monitored or prescribed a lower medication dose. The seemingly paradoxical findings of increased “side effects” at baseline must be considered when monitoring side effects and designing clinical trials.
PMCID: PMC2705008  PMID: 19564304
leukemia; brain tumor; methylphenidate; stimulant; side effects

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