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1.  Proximal dentatothalamocortical tract involvement in posterior fossa syndrome 
Brain  2009;132(11):3087-3095.
Posterior fossa syndrome is characterized by cerebellar dysfunction, oromotor/oculomotor apraxia, emotional lability and mutism in patients after infratentorial injury. The underlying neuroanatomical substrates of posterior fossa syndrome are unknown, but dentatothalamocortical tracts have been implicated. We used pre- and postoperative neuroimaging to investigate proximal dentatothalamocortical tract involvement in childhood embryonal brain tumour patients who developed posterior fossa syndrome following tumour resection. Diagnostic imaging from a cohort of 26 paediatric patients previously operated on for an embryonal brain tumour (13 patients prospectively diagnosed with posterior fossa syndrome, and 13 non-affected patients) were evaluated. Preoperative magnetic resonance imaging was used to define relevant tumour features, including two potentially predictive measures. Postoperative magnetic resonance and diffusion tensor imaging were used to characterize operative injury and tract-based differences in anisotropy of water diffusion. In patients who developed posterior fossa syndrome, initial tumour resided higher in the 4th ventricle (P = 0.035). Postoperative magnetic resonance signal abnormalities within the superior cerebellar peduncles and midbrain were observed more often in patients with posterior fossa syndrome (P = 0.030 and 0.003, respectively). The fractional anisotropy of water was lower in the bilateral superior cerebellar peduncles, in the bilateral fornices, white matter region proximate to the right angular gyrus (Tailerach coordinates 35, –71, 19) and white matter region proximate to the left superior frontal gyrus (Tailerach coordinates –24, 57, 20). Our findings suggest that multiple bilateral injuries to the proximal dentatothalamocortical pathways may predispose the development of posterior fossa syndrome, that functional disruption of the white matter bundles containing efferent axons within the superior cerebellar peduncles is a critical underlying pathophysiological component of posterior fossa syndrome, and that decreased fractional anisotropy in the fornices and cerebral cortex may be related to the abnormal neurobehavioural symptoms of posterior fossa syndrome.
doi:10.1093/brain/awp241
PMCID: PMC2781745  PMID: 19805491
posterior fossa; cerebellum; mutism; medulloblastoma
2.  Evolution of Neurological Impairment in Pediatric Infratentorial Ependymoma Patients 
Journal of neuro-oncology  2009;94(3):391-398.
Background
Infratentorial ependymoma is a common central nervous system tumor of childhood and in patients > 1 year of age is treated with maximally feasible surgical resection and radiotherapy. Because of this tumor typically arises within the 4th ventricle and can invade the brainstem, patients are at risk for significant neurological impairment.
Purpose
To characterize the incidence, evolution, and persistence of neurologic impairment in children with infratentorial ependymoma following maximal safe surgery and conformal or intensity-modulated radiation therapy (CRT/IMRT).
Patients and Methods
After surgical resection, 96 children with non-metastatic infratentorial ependymoma were enrolled on a phase II study of image-guided radiation therapy and were prospectively followed with interval comprehensive neurological examinations. Late adverse neurological severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.
Results
The most common deficits detected at baseline examination were limb dysmetria, cranial nerve VI/VII palsy, limb paresis, dysphagia, and truncal ataxia/hypotonia. When present, gait dysfunction and dysphagia were often severe. Oculomotor dysfunction, facial paresis, dysphagia, and gait impairment improved over time. With the exception of hearing loss, in the survivor cohort, very few severe late effects (CTCAE Grade 3/4/5) were present at 60 month survival.
Conclusion
In general, neurological deficits were maximal in the post-operative period and either remained stable or improved during radiation and the post-treatment evaluation period. With the exception of hearing, the majority of chronic residual neurological deficits in this at-risk population are mild and only minimally intrude upon daily life.
doi:10.1007/s11060-009-9866-8
PMCID: PMC2731005  PMID: 19330288
ependymoma; children; conformal radiation; neurological impairment
4.  Alexander Disease: An Important Mimicker of Focal Brainstem Glioma 
Pediatric blood & cancer  2009;53(7):1355-1356.
We report the case of a 6 year old male who was referred to a tertiary oncology center with a focal brainstem lesion which was presumed to be neoplastic. Due to the symmetric nature of the lesion on magnetic resonance imaging, the evaluation was expanded to investigate other possible causes and eventual diagnosis of Alexander’s disease was made. Alexander disease is a neurodegenerative disease which must be included in the differential for tumor-like lesions within the posterior fossa.
doi:10.1002/pbc.22232
PMCID: PMC2774853  PMID: 19672978
Brainstem glioma; Alexander’s disease; brain tumor mimic; neuro-oncology
5.  Bone Marrow Transplantation for Severe Aplastic Anemia Secondary to Temozolomide 
Journal of neuro-oncology  2008;91(2):237-239.
Radiotherapy (RT) and concomitant/adjuvant therapy with temozolomide (Temodar) is a common treatment regimen for children and adults with glioma. Although temozolomide is generally well tolerated with temporary myelosuppression as the primary dose-limiting toxicity, irreversible bone-marrow aplasia after treatment with temozolomide has been reported. We report the case of an adolescent patient with a high-grade glioma who, after > 2 years of event-free survival, underwent successful bone marrow transplantation for treatment of temozolomide-induced severe aplastic anemia (SAA).
doi:10.1007/s11060-008-9704-4
PMCID: PMC2736860  PMID: 18818880
7.  PET-CT of the Normal Spinal Cord in Children 
Academic radiology  2009;16(7):881-885.
Rationale and Objectives
To assess the correlation between age and spinal cord metabolic activity in children using positron emission tomography-computed tomography.
Materials and Methods
The cohort included 128 children imaged from January 2003 through April 2007, excluding those with spinal disease. Using axial images we subjectively graded as minimal, moderate or intense, the fluorodeoxyglucose activity in the pons and three cervical, three thoracic, and two lumbar spinal cord levels. From regions of interest at each level, we determined the maximum standardized uptake value. Patients were grouped by age: Group 1, < 5 years; Group 2, ≥ 5 to < 10 years; Group 3, ≥10 to <15 years; and Group 4, ≥15 < 22 years. We compared subjective grade and standardized uptake values at each level and for each level between age groups. Alpha was set at 0.0046 based on the Bonferroni correction for multiple comparisons.
Results
There were 16 patients in Group 1, 19 in Group 2, 33 in Group 3, and 60 in Group 4. Subjective grade and standardized uptake values were higher in the pons, mid cervical and low thoracic areas than elsewhere in all age groups. Subjective grade significantly increased with age in the cervical and thoracic cord (P <0.0005). Standardized uptake values in the pons and all cord levels significantly increased with increasing age (P≤0.0008).
Conclusions
In children, metabolic activity of the spinal cord increases with age. On positron emission tomography, the cord can appear intensely avid in the mid cervical and low thoracic areas.
doi:10.1016/j.acra.2009.01.022
PMCID: PMC3680129  PMID: 19427802
positron emission tomography-computed tomography; spinal cord; children
8.  Neuromuscular impairments in adult survivors of childhood acute lymphoblastic leukemia: associations with physical performance and chemotherapy doses 
Cancer  2011;118(3):828-838.
Introduction
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1002/cncr.26337
PMCID: PMC3197897  PMID: 21766297
Acute Lymphoblastic Leukemia; Survivor; Neuromuscular impairment; Function; Physical performance; Intrathecal methotrexate; Vincristine; Late effect
9.  Dysembryoplastic Neuroepithelial Tumors and Cognitive Outcome: cure at a price? 
Cancer  2010;116(23):5461-5469.
Background
Dysembryoplastic neuroepithelial tumors (DNETs) are benign glioneuronal tumors that occur in children. These tumors are characterized by seizures, lack of neurologic deficits, and a seemingly benign course after resection.
Methods
We conducted a retrospective review of data relating to 11 children diagnosed with DNET between January 1988 and December 2007 at St. Jude Children's Research Hospital. This report documents the clinical features, neurocognitive function, and treatment outcomes in our institutional series.
Results
Our patient cohort included 8 boys and 3 girls (median age at diagnosis, 10 years); all patients presented with seizures: 4 complex partial, 3 generalized tonic clonic, 2 absence, 1 partial simple, and 1 not classified. Of the 11 patients, 1 died of cardiac fibrosis, and tumors recurred or progressed in 4 (36%). Seizure control was achieved in all patients but 1. Of the 9 patients who completed neuropsychologic testing, only 3 (23%) functioned at or above the expected level of same-age peers.
Conclusion
The high recurrence and progression rates of DNETs and the high rate of abnormal neurocognitive test results in this study highlight the need for regular follow-up and appropriate academic counseling of children with these tumors.
doi:10.1002/cncr.25528
PMCID: PMC3556450  PMID: 20672357
Dysembryoplastic neuroepithelial tumors (DNETs); pediatric; recurrence; neuropsychologic outcome
10.  Physical performance limitations among adult survivors of childhood brain tumors 
Cancer  2010;116(12):3034-3044.
Background
Young adult survivors of childhood brain tumors (BT) may have late-effects that compromise physical performance and everyday task participation.
Objective
To evaluate muscle strength, fitness, physical performance, and task participation among adult survivors of childhood BT.
Design/Method
In-home evaluations and interviews were conducted for 156 participants (54% male). Results on measures of muscle strength, fitness, physical performance, and participation were compared between survivors and population-group members with chi-squared statistics and two-sample t-tests. Associations between late effects and physical performance, and physical performance and participation, were evaluated in regression models.
Results
BT survivors were a median age of 22 (18–58), and 14.7 (6.5–45.9) years from diagnosis. Survivors had lower estimates of grip strength (Female: 24.7±9.2 vs. 31.5±5.8, Male: 39.0±12.2 vs. 53.0±10.1 kilograms), knee extension strength (Female: 246.6±95.5 vs. 331.5±5.8, Male: 304.7±116.4 vs. 466.6±92.1 Newtons) and peak oxygen uptake (Female: 25.1±8.8 vs. 31.3±5.1, Male: 24.6±9.5 vs. 33.2±3.4 milliliters/kilogram/minute) than population-group members. Physical performance was lower among survivors and associated with not living independently (OR=5.0, 95% CI=2.0–12.2) and not attending college (OR=2.3, 95% CI 1.2–4.4).
Conclusion
Muscle strength and fitness values among BT survivors are similar to those among persons 60+ years, and are associated with physical performance limitations. Physical performance limitations are associated with poor outcomes in home and school environments. These data indicate an opportunity for interventions targeted at improving long-term physical function in this survivor population.
doi:10.1002/cncr.25051
PMCID: PMC3554250  PMID: 20564409
physical performance; disability; brain tumor; cancer survivor; pediatric
11.  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
12.  Prospective Medical Assessment of Adults Surviving Childhood Cancer: Study Design, Cohort Characteristics, and Feasibility of the St. Jude Lifetime Cohort Study 
Pediatric blood & cancer  2010;56(5):825-836.
Background
To facilitate prospective medical assessment of adults surviving pediatric malignancies and advance knowledge about long-term childhood cancer survivor health, St. Jude Children’s Research Hospital (SJCRH) is establishing a lifetime cohort of survivors.
Methods
Eligibility criteria for inclusion in the St. Jude Lifetime Cohort (SJLIFE) study include: 1) diagnosis of childhood malignancy treated at SJCRH; 2) survival ≥ 10 years from diagnosis; and 3) current age ≥ 18 years. Three levels of participation are offered: 1) comprehensive evaluation on SJCRH campus; 2) limited home evaluation; or 3) completion of health surveys only. A systematic recruitment structure based upon blocks of 50 patients initially focused on leukemia and lymphoma survivors and patients eligible for pilot studies.
Results
As of 01/01/2010, 1625 (42%) of 3900 eligible ≥ 10 year survivors have been contacted. Among the first 1000 potentially eligible survivors selected for recruitment, 971 were subsequently confirmed to fulfill eligibility criteria. To date, 898/971 (92.5%) have been successfully contacted of whom 825 (91.8%) have agreed to participate. Among participants, 88.6% agreed to comprehensive medical evaluation, 0.4% limited local evaluation, and 11.0% survey only. Anticipated minimum overall participation rate for medical evaluation is 75.3% (731/971). Comparison of those contacted who agreed versus declined to participate revealed a greater proportion of males who declined participation (p = 0.001).
Conclusions
Early results of the SJLIFE study support its feasibility to recruit aging childhood cancer survivors to research investigations evaluating late health outcomes by medical assessments.
doi:10.1002/pbc.22875
PMCID: PMC3088729  PMID: 21370418
Childhood cancer; late effects; long-term follow-up
13.  Survival and long-term health and cognitive outcomes after low-grade glioma 
Neuro-Oncology  2010;13(2):223-234.
Long-term morbidity for children with low-grade glioma (LGG) requires exposure-specific characterization. Overall survival (OS) and progression-free survival (PFS) were estimated for 361 children diagnosed with LGG between 1985 and 2007 at a single institution. Five-year survivors (n = 240) received risk-based clinical assessment. Cumulative incidence of late effects 15 years from diagnosis were estimated. Risk factors for adverse health were identified using Fine and Gray's approach to Cox's proportional hazards model, accounting for death as a competing risk. OS at 15 years was 86% (95% confidence interval [CI] 82%–90%), and PFS was 55% (95% CI 51%–58%). Among the 240 5-year survivors, the 5-, 10-, and 15-year cumulative incidence of adverse outcomes included blindness: 10%, 13%, and 18%, respectively; hearing loss: 8%, 14%, and 22%; obesity/overweight: 18%, 35%, and 53%; hyperinsulinism: 1%, 5%, and 24%; growth hormone deficiency: 13%, 27%, and 29%;thyroid hormone deficiency: 16%, 28%, and 33%; and adrenocorticotropic hormone (ACTH) deficiency: 12%, 22%, and 26%. Multivariable models demonstrated radiation therapy to be a significant independent predictor of hearing loss, growth hormone deficiency, abnormal thyroid function, and ACTH deficiency. Diencephalic location was a statistically significant independent risk factor for blindness, growth hormone deficiency, abnormal thyroid function, and ACTH deficiency. Among the 182 5-year survivors assessed for intellectual function, 34% had an intelligence quotient (IQ) below average (<85), associated with younger age at diagnosis, epilepsy, and shunt placement. Survivors of childhood LGG experience substantial long-term adverse effects that continue to increase well beyond the 5-year survival time point.
doi:10.1093/neuonc/noq178
PMCID: PMC3064628  PMID: 21177781
cancer; glioma; pediatric; survivor
14.  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.
Purpose
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.
Results
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.
Conclusion
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.
doi:10.1200/JCO.2010.28.4026
PMCID: PMC2988638  PMID: 20837955
15.  Prospective Collection of Tissue Samples at Autopsy in Children with Diffuse Intrinsic Pontine Glioma 
Cancer  2010;116(19):4632-4637.
BACKGROUND
Brain tissue obtained at autopsy has been used in research for non-oncological disorders. However, this tool has never been systematically used in large investigational studies for cancer. We conducted a prospective, multicenter study to assess the feasibility of tissue collection at autopsy and its suitability for molecular analyses in children with diffuse intrinsic pontine glioma.
METHODS
Tumor tissue was collected at diagnosis, if clinically indicated, or at autopsy. Normal brain tissue was also collected at autopsy. The integrity of DNA and RNA was evaluated in all samples. Logistical data about autopsies were recorded. The feasibility of tissue collection at autopsy was assessed for patients treated at a single institution over a 43-month period.
RESULTS
Tumor samples were collected at diagnosis (n=3) or at autopsy (n=38) at 29 centers across the US; samples were obtained at diagnosis and autopsy in two cases. The median interval from death to autopsy was 7.7 hours. DNA and RNA with minimal or partial degradation, which were suitable for genome-wide analysis, were obtained from 100% and 63% of tumor samples, respectively. At the coordinating institution, approximately 40% of parents consented to autopsy and 40% declined. During the study period, 12 autopsies were obtained from patients who did not receive therapy at the coordinating center.
CONCLUSIONS
Multicenter, biological studies based on tissue obtained at autopsy are feasible in children with brain cancer. Our experience established a new paradigm for brain tissue collection which may increase the potential for research studies in patients with cancer.
doi:10.1002/cncr.25405
PMCID: PMC2989604  PMID: 20589749
autopsy; brain; children; diffuse intrinsic pontine glioma; molecular studies
16.  Side Effects of Methylphenidate in Survivors of Childhood Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial 
Pediatrics  2009;124(1):226-233.
OBJECTIVES
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.
PARTICIPANTS AND METHODS
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.
RESULTS
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).
CONCLUSIONS
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.
doi:10.1542/peds.2008-1855
PMCID: PMC2705008  PMID: 19564304
leukemia; brain tumor; methylphenidate; stimulant; side effects
17.  Sperm Cryopreservation Practices Among Adolescent Cancer Patients At Risk For Infertility 
Pediatric hematology and oncology  2009;26(4):252-260.
To assess sperm cryopreservation among males newly diagnosed with cancer aged 13 years and older, attending oncologists assigned infertility risk (yes/no) to patients and reported whether their patients engaged in sperm cryopreservation. Only 28.1% of informed at-risk patients banked sperm. Utilization of sperm banking was significantly associated with a diagnosis of CNS malignancy or non-CNS solid tumor diagnosis, higher socioeconomic status, and not being a member of an Evangelical religious group. These results suggest that sperm banking is underutilized among adolescent males newly diagnosed with cancer, and that strategies to increase the engagement in this fertility preservation method are needed.
doi:10.1080/08880010902901294
PMCID: PMC2801903  PMID: 19437327
sperm cryopreservation; fertility; assisted reproduction; childhood cancer
18.  Recurrent Intrathecal Methotrexate Induced Neurotoxicity in an Adolescent with Acute Lymphoblastic Leukemia: Serial Clinical and Radiologic Findings 
Pediatric blood & cancer  2009;52(2):293-295.
Systemic and intrathecal methotrexate (MTX) are integral components of acute lymphoblastic leukemia (ALL) therapy, but can be associated with neurotoxicity. We describe here the case of an adolescent male with T-cell ALL who developed recurrent episodes of subacute neurotoxicity characterized by slurred speech, emotional lability, and hemiparesis after intrathecal MTX administration. Serial magnetic resonance imaging with diffusion-weighted imaging showed recurrent areas of restricted diffusion within cerebral hemispheric white matter, which correlated chronologically with the administration of intrathecal therapy and severity of clinical symptoms. Resolution of diffusion abnormalities did not preclude further toxicity and a large lesion could cause persisting symptoms.
doi:10.1002/pbc.21764
PMCID: PMC2605174  PMID: 18831032
methotrexate; neurotoxicity; leukemia; diffusion-weighted imaging; intrathecal therapy; magnetic resonance imaging
19.  Phase I and Pharmacokinetic Studies of Erlotinib Administered Concurrently With Radiotherapy for Children, Adolescents, and Young Adults with High-Grade Glioma 
STATEMENT OF TRANSLATIONAL RELEVANCE
Although chemotherapy has been used in most clinical trials for children with high-grade glioma, no drug regimen has so far stood out as particularly beneficial for these patients.
Based on pre-clinical and clinical experience in adults with similar tumors, we report for the first time the results of a Phase I study which used erlotinib during and after radiotherapy in children with high-grade glioma. We characterized the acute and chronic toxicities associated with erlotinib therapy. Within the context of a Phase I study, we also performed extensive pharmacokinetic and molecular studies.
We observed preliminary encouraging outcome in a subgroup of our patients, particularly those with anaplastic astrocytoma. Therefore, the current study established a platform for future clinical trials to incorporate erlotinib in the treatment of high-grade glioma in children.
Purpose
To estimate the maximum-tolerated dose (MTD) of erlotinib administered during and after radiotherapy (RT), and to describe the pharmacokinetics of erlotinib and its metabolite OSI-420 in patients between 3 and 25 years with newly diagnosed high-grade glioma who did not require enzyme-inducing anticonvulsants.
Experimental Design
Five dosage levels (70, 90, 120, 160, and 200mg/m2 per day) were planned in this Phase I study. Dose-limiting toxicities (DLTs) were evaluated during first 8 weeks of therapy. Local RT (dose between 54 and 59.4 Gy) and erlotinib started preferentially on the same day. Erlotinib was administered once daily for a maximum of 3 years. Pharmacokinetic studies were obtained after first dose and on day 8 of therapy. Mutational analysis of EGFR kinase domain, PIK3CA, and PTEN was performed in tumor tissue.
Results
Median age at diagnosis of 23 patients was 10.7 years (range, 3.7 to 22.5 years). MTD of erlotinib was 120mg/m2 per day. Skin rash and diarrhea were generally well controlled with supportive care. DLTs were diarrhea (n=1), increase in serum lipase (n=1), and rash with pruritus (n=1). The pharmacokinetic parameters of erlotinib and OSI-420 in children were similar to those described in adults. However, there was no relationship between erlotinib dosage and drug exposure. No EGFR kinase domain mutations were observed. Two patients with glioblastoma harbored mutations in PIK3CA (n=1) or PTEN (n=1).
Conclusions
Although the MTD of erlotinib in children with newly diagnosed high-grade glioma was 120mg/m2 per day, pharmacokinetic studies demonstrated wide inter-patient variability in drug exposure.
doi:10.1158/1078-0432.CCR-08-1923
PMCID: PMC2629527  PMID: 19147777
children; erlotinib; glioma; high-grade; radiotherapy
20.  Growth Effects of Methylphenidate Among Childhood Cancer Survivors: A 12-Month Case-Matched Open-Label Study 
Pediatric blood & cancer  2009;52(1):39-43.
Background
To investigate the effect of stimulant medication [methylphenidate (MPH)] on growth patterns among survivors of childhood cancer (acute lymphoblastic leukemia or brain tumor).
Procedure
Using a case-matched comparison design, childhood cancer survivors participating in a 12-month open-label MPH trial (n = 51) were compared with childhood cancer survivors not taking MPH (n = 51). Measures of body mass index (BMI), height, and weight were obtained at hospital visits and corrected for gender and age using Centers for Disease Control normative data.
Results
Significant deceleration of BMI and weight, but not height, was observed during the 12-month MPH trial for those children taking MPH.
Conclusions
Childhood cancer survivors taking MPH experience significant, though modest, deceleration of BMI and weight across the first year of MPH intervention. The absence of height deceleration, and the presence of only modest BMI and weight deceleration, suggests that MPH is reasonably well tolerated by childhood cancer survivors with respect to growth. Such findings are encouraging in light of increasing evidence that MPH mitigates some of the cognitive late-effects of cancer treatments. Nevertheless, on a case-by-case basis, clinicians should balance the intended benefits of MPH with potential growth effects in this vulnerable population.
doi:10.1002/pbc.21770
PMCID: PMC2585147  PMID: 18855893
leukemia; brain tumor; methylphenidate; growth
21.  M1 Medulloblastoma: High Risk at any Age 
Journal of neuro-oncology  2008;90(3):351-355.
Background
The prognosis for children with M1 medulloblastoma (positive CSF cytology) has not been well-defined.
Methods
We retrospectively reviewed the records of 285 newly diagnosed medulloblastoma patients treated between 1984 and 2006. Older children received post-operative craniospinal and tumor bed irradiation; radiotherapy for younger children depended on treatment era and physician/family preference.
Results
55 patients were <3 years old and 230 patients were = 3 years old at diagnosis. We detected significant (p<0.0001) associations between M1 disease and EFS for the entire cohort and for both younger and older patients. Among younger children, M1 patients had lower EFS than M0 (p=0.0044).
Conclusions
Children <3 years old with M1 medulloblastoma fared poorly in our small series. Survival for older children with M1 disease treated with higher-dose CSI was better than that of M2/M3 patients, but still less than optimal; our findings do not support reduction in therapy for either cohort.
doi:10.1007/s11060-008-9671-9
PMCID: PMC2597631  PMID: 18704266
medulloblastoma; cytology; infant; survival; metastatic; prognosis
22.  Childhood central nervous system leukemia: historical perspectives, current therapy, and acute neurological sequelae 
Neuroradiology  2007;49(11):873-888.
Introduction
During the past three decades, improvements in the treatment of childhood leukemia have resulted in high cure rates, particularly for acute lymphoblastic leukemia (ALL). Unfortunately, successful therapy has come with a price, as significant morbidity can result from neurological affects which harm the brain and spinal cord. The expectation and hope is that chemotherapy, as a primary means of CNS therapy, will result in acceptable disease control with less CNS morbidity than has been observed with combinations of chemotherapy and radiotherapy over the past several decades.
Methods and results
In this review we discuss the poignant, historical aspects of CNS leukemia therapy, outline current methods of systemic and CNS leukemia therapy, and present imaging findings we have encountered in childhood leukemia patients with a variety of acute neurological conditions. A major objective of our research is to understand the neuroimaging correlates of acute and chronic effects of cancer and therapy. Specific features related to CNS leukemia and associated short-term toxicities, both disease- and therapy-related, are emphasized in this review with the specific neuroimaging findings. Specific CNS findings are similarly important when treating acute myelogenous leukemia (AML), and details of leukemic involvement and toxicities are also presented in this entity.
Conclusion
Despite contemporary treatment approaches which favor the use of chemotherapy (including intrathecal therapy) over radiotherapy in the treatment of CNS leukemia, children still occasionally experience morbid neurotoxicity. Standard neuroimaging is sufficient to identify a variety of neurotoxic sequelae in children, and often suggest specific etiologies. Specific neuroimaging findings frequently indicate a need to alter antileukemia therapy. It is important to appreciate that intrathecal and high doses of systemic chemotherapy are not innocuous and are associated with acute, specific, recognizable, and often serious neurological consequences.
doi:10.1007/s00234-007-0300-7
PMCID: PMC2386669  PMID: 17924103
Childhood CNS leukemia; Neurotoxicity; Intrathecal therapy; CNS infection; Secondary malignancies; Methotrexate

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