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1.  RELAPSE AFTER TREATMENT OF PEDIATRIC HODGKIN LYMPHOMA: Outcome and Role of Surveillance After End of Therapy 
Pediatric blood & cancer  2013;60(9):1458-1463.
Background
The outcome of treatment for pediatric Hodgkin lymphoma (HL) is excellent using chemotherapy and radiation. However, a minority of patients will relapse after treatment, but additional therapy achieves durable second remission in many cases. The optimal surveillance strategy after modern therapy for HL has not been well-defined.
Procedures
We reviewed the outcomes of pediatric patients with HL treated between 1990 and 2006 to determine the primary event that led to the detection of relapse. We determined the probability of relapse detection by routine follow-up procedures, including history, physical examination, laboratory tests, and imaging, and determined the impact of each of these screening methods on the likelihood of survival after relapse.
Results
Relapse occurred in 64 of 402 evaluable patients (15.9%) at a median of 1.7 years from the time of diagnosis. The majority of relapses (60%) were diagnosed at a routine visit, and patient complaint was the most common initial finding that led to a diagnosis of relapse (47% of relapses). An abnormal finding on physical examination was the primary event in another 17% of relapses, and imaging abnormalities led to the diagnosis in the remaining 36%. Laboratory abnormalities were never the primary finding. The method of detection of relapse and timing (whether detected at a routine visit or an extra visit) did not impact survival.
Conclusions
In pediatric Hodgkin lymphoma, most relapses are identified through history and physical examination. Frequent imaging of asymptomatic patients does not appear to impact survival and is probably not warranted.
doi:10.1002/pbc.24568
PMCID: PMC4313350  PMID: 23677874
pediatric; childhood; Hodgkin lymphoma; relapse; surveillance; outcome
2.  Long-Term Outcome and Risk Factors for Uncontrolled Seizures After a First Seizure in Children With Hematological Malignancies 
Journal of child neurology  2013;29(6):774-781.
Long-term outcomes of seizures that develop during treatment of childhood hematological malignancies have not been described. We analyzed seizure outcome in 62 children with leukemia or lymphoma treated at our institution. There was a median follow-up of 6.5 years since first seizure. Seizure etiology included intrathecal or systemic methotrexate in 24, leucoencephalopathy in 11, brain hemorrhage or thrombosis in 11, meningitis in 4, and no identifiable cause in 12. Seizures remained uncontrolled in 18, and risk factors for poor control included female sex (P = .02), no seizure control with first antiseizure drug (P = .08), and longer interval between cancer diagnosis and seizure onset (P = .09). Poor seizure control after initial antiseizure drug also predicted recurrent seizure after drug withdrawal (P = .04). In conclusion, seizures are controlled with medications in a majority of patients with hematological cancer. After a period without seizures, antiseizure drug withdrawal in appropriately selected patient has a high success rate.
doi:10.1177/0883073813488675
PMCID: PMC4207712  PMID: 23666043
leukemia; lymphoma; seizures; outcome; hematological malignancy; methotrexate
4.  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
doi:10.1371/journal.pmed.1001656
PMCID: PMC4061014  PMID: 24936984
5.  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.
Background
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1002/cncr.28026
PMCID: PMC3862024  PMID: 23456849
acute lymphoblastic leukemia; lymphocytes; pediatrics; prognosis
6.  Management of children with brain tumors in Paraguay 
Neuro-Oncology  2012;15(2):235-241.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1093/neuonc/nos291
PMCID: PMC3548583  PMID: 23197688
brain tumors; children; low-income country; Paraguay
7.  Effect of Body Mass Index on the Outcome of Children with Acute Myeloid Leukemia 
Cancer  2012;118(23):5989-5996.
BACKGROUND
The effect of body mass index (BMI) on treatment outcome of children with acute myeloid leukemia (AML) is unclear and needs further evaluation.
METHODS
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).
RESULTS
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).
CONCLUSIONS
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.
doi:10.1002/cncr.27640
PMCID: PMC3434283  PMID: 22648558
body mass index; children; acute myeloid leukemia; survival; toxicity
8.  Resumption of High-dose Methotrexate after Acute Kidney Injury and Glucarpidase Use in Pediatric Oncology Patients 
Cancer  2012;118(17):4321-4330.
Background
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.
Methods
Clinical data and outcomes of all patients who received glucarpidase after HDMTX administration were reviewed.
Results
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.
Conclusion
It is possible to safely resume HDMTX therapy after glucarpidase treatment for HDMTX-induced acute kidney injury.
doi:10.1002/cncr.27378
PMCID: PMC3713608  PMID: 22252903
Carboxypeptidases; gamma-Glutamyl hydrolase; methotrexate/administration and dosage; methotrexate/adverse effects; compassionate use trials; renal insufficiency/chemically induced; pediatric
9.  Development and use of active clinical decision support for preemptive pharmacogenomics 
Background
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.
Objective
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.
Results
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.
Conclusions
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.
doi:10.1136/amiajnl-2013-001993
PMCID: PMC3957400  PMID: 23978487
pharmacogenetics; electronic health record; clinical decision support; personalized medicine
10.  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.
Background
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.
Conclusion
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.
doi:10.1186/1471-2431-13-103
PMCID: PMC3717068  PMID: 23841990
Mediastinal disease; Mediastinum; Positron-emission tomography; Thymus hyperplasia
11.  Between-course targeting of methotrexate exposure using pharmacokinetically guided dosage adjustments 
Purpose
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1007/s00280-013-2206-x
PMCID: PMC3719000  PMID: 23760811
Methotrexate; Acute lymphoblastic leukemia; Pharmacokinetics; Individualized therapy
12.  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.
Purpose
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.
Results
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.
Conclusion
With equal access to comprehensive treatment, black and white children with cancer can achieve the same high cure rates.
doi:10.1200/JCO.2011.40.8617
PMCID: PMC3383176  PMID: 22547602
14.  A Clinician-Driven Automated System for Integration of Pharmacogenetic Consults into an Electronic Medical Record 
doi:10.1038/clpt.2012.140
PMCID: PMC3589522  PMID: 22990750
pharmacogenetics; electronic medical record; personalized medicine; cytochrome P450 2D6; thiopurine-methyltransferase
15.  Clinical consequences of hyperglycemia during remission induction therapy for pediatric acute lymphoblastic leukemia 
Hyperglycemia adversely affects outcomes in adult patients with acute lymphoblastic leukemia (ALL), but its impact on children with this disease is unknown. We evaluated the relationship between hyperglycemia during remission induction therapy and clinical outcomes among pediatric patients with ALL. We reviewed the records of patients enrolled on four consecutive ALL protocols (Total Therapy protocols XIIIA, XIIIB, XIV, and XV) at St. Jude Children's Research Hospital from 1991 to 2007 and identified those who experienced hyperglycemia (glucose ≥200 mg/dL) during remission induction. Complete remission rates at the end of induction, event free survival, overall survival, cumulative incidence of relapse, and occurrence of infections were compared between those who did and did not experience hyperglycemia. Of 871 patients analyzed, 141 (16%) experienced hyperglycemia during remission induction. Patients with hyperglycemia were significantly older than the other patients (p<0.0001). There was no significant difference in complete remission rate (p=0.92), event-free survival (p=0.80), overall survival (p=0.28), cumulative incidence of relapse (p=0.59), or in the probability or types of infection between patients who did and did not experience hyperglycemia. Pediatric patients with or without hyperglycemia during remission induction for ALL have similar clinical outcome. Occurrence of hyperglycemia does not warrant alteration of the antileukemic regimen.
doi:10.1038/leu.2008.289
PMCID: PMC2706830  PMID: 18923438
Pediatric Oncology; Acute lymphoblastic leukemia; Infections; Hyperglycemia; Supportive care
16.  Healthcare-Associated Infections at a Children's Cancer Hospital, 1983–2008 
Background.
Little is known about the incidence and etiology of healthcare-associated infections in immunosuppressed children.
Methods.
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.
Results.
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.
Conclusions.
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.
doi:10.1093/jpids/pis034
PMCID: PMC3656547  PMID: 23687571
17.  ETV6-RUNX1-positive childhood acute lymphoblastic leukemia: improved outcome with contemporary therapy 
Leukemia  2011;26(2):265-270.
ETV6-RUNX1 fusion is the most common genetic aberration in childhood acute lymphoblastic leukemia (ALL). To evaluate whether outcomes for this drug-sensitive leukemia are improved by contemporary risk-directed therapy, we studied clinical features, response and adverse events of 168 children with newly diagnosed ETV6-RUNX1-positive ALL on St Jude Total Therapy studies XIIIA (N=36), XIIIB (N=38) and XV (N=94). Results were compared to 494 ETV6-RUNX1-negative B-precursor ALL patients. ETV6-RUNX1 was associated with age 1-9 years, pre-treatment classification as low-risk and lower levels of minimal residual disease (MRD) on day 19 of therapy (p<0.001). Event-free survival (EFS) or overall survival (OS) did not differ between patients with or without ETV6-RUNX1 in Total XIIIA or XIIIB. By contrast, in Total XV, patients with ETV6-RUNX1 had significantly better EFS (p=0.04; 5-year estimate, 96.8±2.4% versus 88.3±2.5%) and OS (p=0.04; 98.9±1.4% versus 93.7±1.8%) than those without ETV6-RUNX1. Within the ETV6-RUNX1 group, the only significant prognostic factor associated with higher OS was the treatment protocol Total XV (versus XIIIA or XIIIB) (p=0.01). Thus, the MRD-guided treatment schema including intensive asparaginase and high-dose methotrexate in the Total XV study produced significantly better outcomes than previous regimens and demonstrated that nearly all children with ETV6-RUNX1 ALL can be cured.
doi:10.1038/leu.2011.227
PMCID: PMC3345278  PMID: 21869842
leukemia; ETV6-RUNX1; TEL-AML1
19.  ASSOCIATION BETWEEN RADIOTHERAPY VS NO RADIOTHERAPY BASED ON EARLY RESPONSE TO VAMP CHEMOTHERAPY AND SURVIVAL AMONG CHILDREN WITH FAVORABLE RISK HODGKIN LYMPHOMA 
Context
Maintaining excellent cure rates in pediatric Hodgkin lymphoma while minimizing toxicity.
Objective
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.
Interventions
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.
Results
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.
Conclusions
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.
doi:10.1001/jama.2012.5847
PMCID: PMC3526806  PMID: 22735430
20.  Symptoms of Attention-Deficit/Hyperactivity Disorder in Long-Term Survivors of Childhood Leukemia 
Pediatric blood & cancer  2011;57(7):1191-1196.
Background
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.
Procedure
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.
Results
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).
Conclusions
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.
doi:10.1002/pbc.22994
PMCID: PMC3140624  PMID: 21280202
ALL; long-term survivor; Attention-Deficit/Hyperactivity Disorder
21.  Severe Thrombocytopenia with Iron Deficiency Anemia 
Pediatric hematology and oncology  2010;27(5):413-419.
Objective
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.
Methods
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.
doi:10.3109/08880011003739455
PMCID: PMC3439835  PMID: 20670168
Anemia; iron deficiency; thrombocytopenia; children
22.  The Tumor Lysis Syndrome 
The New England journal of medicine  2011;364(19):1844-1854.
doi:10.1056/NEJMra0904569
PMCID: PMC3437249  PMID: 21561350
23.  Low Socioeconomic Status Is Associated with Prolonged Times to Assessment and Treatment, Sepsis and Infectious Death in Pediatric Fever in El Salvador 
PLoS ONE  2012;7(8):e43639.
Background
Infection remains the most common cause of death from toxicity in children with cancer in low- and middle-income countries. Rapid administration of antibiotics when fever develops can prevent progression to sepsis and shock, and serves as an important indicator of the quality of care in children with acute lymphoblastic leukemia and acute myeloid leukemia. We analyzed factors associated with (1) Longer times from fever onset to hospital presentation/antibiotic treatment and (2) Sepsis and infection-related mortality.
Method
This prospective cohort study included children aged 0–16 years with newly diagnosed acute leukemia treated at Benjamin Bloom Hospital, San Salvador. We interviewed parents/caregivers within one month of diagnosis and at the onset of each new febrile episode. Times from initial fever to first antibiotic administration and occurrence of sepsis and infection-related mortality were documented.
Findings
Of 251 children enrolled, 215 had acute lymphoblastic leukemia (85.7%). Among 269 outpatient febrile episodes, median times from fever to deciding to seek medical care was 10.0 hours (interquartile range [IQR] 5.0–20.0), and from decision to seek care to first hospital visit was 1.8 hours (IQR 1.0–3.0). Forty-seven (17.5%) patients developed sepsis and 7 (2.6%) died of infection. Maternal illiteracy was associated with longer time from fever to decision to seek care (P = 0.029) and sepsis (odds ratio [OR] 3.06, 95% confidence interval [CI] 1.09–8.63; P = 0.034). More infectious deaths occurred in those with longer travel time to hospital (OR 1.36, 95% CI 1.03–1.81; P = 0.031) and in families with an annual household income
Interpretation
Illiteracy, poverty, and longer travel times are associated with delays in assessment and treatment of fever and with sepsis and infectious mortality in pediatric leukemia. Providing additional education to high-risk families and staying at a nearby guest house during periods of neutropenia may decrease sepsis and infectious mortality.
doi:10.1371/journal.pone.0043639
PMCID: PMC3425537  PMID: 22928008
Journal of Clinical Oncology  2010;29(4):386-391.
Purpose
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.
Results
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.
Conclusion
Most older adolescents with ALL can be cured with risk-adjusted intensive chemotherapy without stem-cell transplantation.
doi:10.1200/JCO.2010.32.0325
PMCID: PMC3058285  PMID: 21172890
Journal of Palliative Medicine  2010;13(11):1349-1352.
Abstract
Objective
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.
Patients/methods
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.
Results
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.
Conclusions
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.
doi:10.1089/jpm.2010.0177
PMCID: PMC3001240  PMID: 21034279

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