Publications by authors named "Fred Laningham"

32 Publications

Isavuconazole as Salvage Therapy for Refractory Pediatric Coccidioidal Meningitis.

Pediatr Infect Dis J 2021 Mar;40(3):e128-e131

Department of Pediatrics, Stanford University School of Medicine, Stanford.

Coccidioidal meningitis remains difficult to treat. The newer triazole, isavuconazole, has demonstrated efficacy in invasive fungal disease with less side effects than other azoles. We describe a case of refractory pediatric coccidioidal meningitis with disease stabilization and improvement on isavuconazole after failing treatment with other antifungal agents.
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http://dx.doi.org/10.1097/INF.0000000000003017DOI Listing
March 2021

Characterization of Leukoencephalopathy and Association With Later Neurocognitive Performance in Pediatric Acute Lymphoblastic Leukemia.

Invest Radiol 2021 Feb;56(2):117-126

From the Department of Diagnostic Imaging, St Jude Children's Research Hospital, Memphis, TN.

Objectives: The most common form of pediatric cancer is acute lymphoblastic leukemia (ALL). Magnetic resonance (MR) neuroimaging studies have revealed leukoencephalopathy (LE) in pediatric ALL, but the impact of LE on long-term neurocognitive performance remains unknown. This study aims to objectively characterize the prevalence, extent, and intensity of LE, and their association with later neurocognitive performance.

Materials And Methods: Pediatric patients (N = 377) treated for ALL without irradiation underwent MR neuroimaging at 4 time points throughout therapy (end of remission induction [MR1], end of consolidation [MR2], and week 31 [MR3] and week 120 [end therapy, MR4] of continuation treatment) and neurocognitive evaluations at the end of therapy and 2 years later. Generalized estimation equation models with logit link were developed to explore the association between LE prevalence and extent with time points throughout therapy, age at diagnosis (≤5 years or >5 years), treatment risk arm (low risk or standard/high risk), and sex. General linear models were also developed to investigate the association between neuroimaging metrics during treatment and neurocognitive performance at 2-year follow-up.

Results: The prevalence of LE was greatest (22.8%, 74/324) after consolidation therapy. The prevalence of LE increased at MR2 relative to MR1 regardless of treatment risk arm (both P's < 0.001), age group (both P's < 0.001), or sex (male, P < 0.001; female, P = 0.013). The extent of white matter affected also increased at MR2 relative to MR1 regardless of treatment risk arm (standard/high risk, P < 0.001; low risk, P = 0.004), age group (both P's < 0.001), or sex (male, P < 0.001; female, P = 0.001). Quantitative relaxation rates were significantly longer in LE compared with that in normal-appearing white matter in the same examination (T1, P < 0.001; T2, P < 0.001). The LE prevalence early in therapy was associated with increased parent ratings of conduct problems (P = 0.039) and learning difficulties (P = 0.036) at 2-year follow-up compared with that at the end of therapy. A greater extent of LE early in therapy was associated with decreasing performance on a measure of processing speed (P = 0.003) from the end of therapy to 2-year follow-up. A larger extent of LE at the end of therapy was associated with decreased performance in reading (P = 0.004), spelling (P = 0.003), and mathematics (P = 0.019) at 2-year follow-up and increasing problems with attention (omissions, P = 0.045; β, P = 0.015) and memory (list A total recall, P = 0.010) at 2-year follow-up compared with that at the end of therapy.

Conclusions: In this large cohort of pediatric patients treated for ALL without irradiation, asymptomatic LE during therapy can be seen in almost a quarter of patients, involves as much as 10% of the white matter volume, and is associated with decreasing neurocognitive performance, increasing parent reports of conduct problems, and learning difficulties in survivors.
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http://dx.doi.org/10.1097/RLI.0000000000000715DOI Listing
February 2021

A Case of Lysosomal Acid Lipase Deficiency Confirmed by Response to Sebelipase Alfa Therapy.

J Pediatr Gastroenterol Nutr 2020 12;71(6):726-730

Department of Pathology, University of California San Francisco, San Francisco, CA.

Lysosomal acid lipase (LAL) deficiency, or cholesterol ester storage disease, is a disorder affecting the breakdown of cholesterol esters and triglycerides within lysosomes. Clinical findings include hepatomegaly, hepatic dysfunction, and dyslipidemia with a wide range of phenotypic variability and age of onset. The available clinical and molecular information of the patient presented herein was consistent with a diagnosis of LAL deficiency, but her LAL activity assay repeatedly showed normal or borderline low results. Her response to enzyme replacement therapy and demonstrable deficiency on a newer specific enzymatic assay ultimately confirmed her diagnosis of LAL deficiency.
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http://dx.doi.org/10.1097/MPG.0000000000002870DOI Listing
December 2020

Conformal Radiation Therapy for Pediatric Ependymoma, Chemotherapy for Incompletely Resected Ependymoma, and Observation for Completely Resected, Supratentorial Ependymoma.

J Clin Oncol 2019 04 27;37(12):974-983. Epub 2019 Feb 27.

22 Hospital for Sick Children, Toronto, Ontario, Canada.

Purpose: The Children's Oncology Group trial ACNS0121 estimated event-free survival (EFS) and overall survival for children with intracranial ependymoma treated with surgery, radiation therapy, and-selectively-with chemotherapy. Treatment was administered according to tumor location, histologic grade, and extent of resection. The impacts of histologic grade, focal copy number gain on chromosome 1q, and DNA methylation profiles were studied for those undergoing surgery and immediate postoperative conformal radiation therapy (CRT).

Methods: ACNS0121 included 356 newly diagnosed patients (ages 1 to 21 years). Patients with classic supratentorial ependymoma were observed after gross total resection (GTR). Those undergoing subtotal resection received chemotherapy, second surgery, and CRT. The remaining patients received immediate postoperative CRT after near-total resection or GTR. CRT was administered with a 1.0-cm clinical target volume margin. The cumulative total dose was 59.4 Gy, except for patients who underwent GTR and were younger than age 18 months (who received 54 Gy). Patients were enrolled between October 2003 and September 2007 and were observed for 5 years. Supratentorial tumors were evaluated for fusion; infratentorial tumors, for chromosome 1q gain. Classification of posterior fossa groups A and B was made by methylation profiles.

Results: The 5-year EFS rates were 61.4% (95% CI, 34.5% to 89.6%), 37.2% (95% CI, 24.8% to 49.6%), and 68.5% (95% CI, 62.8% to 74.2%) for observation, subtotal resection, and near-total resection/GTR groups given immediate postoperative CRT, respectively. The 5-year EFS rates differed significantly by tumor grade ( = .0044) but not by age, location, fusion status, or posterior fossa A/posterior fossa B grouping. EFS was higher for patients with infratentorial tumors without 1q gain than with 1q gain (82.8% [95% CI, 74.4% to 91.2%] 47.4% [95% CI, 26.0% to 68.8%]; = .0013).

Conclusion: The EFS for patients with ependymoma younger than 3 years of age who received immediate postoperative CRT and for older patients is similar. Irradiation should remain the mainstay of care for most subtypes.
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http://dx.doi.org/10.1200/JCO.18.01765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186586PMC
April 2019

Neurocognitive outcomes among children who experienced seizures during treatment for acute lymphoblastic leukemia.

Pediatr Blood Cancer 2017 Aug 28;64(8). Epub 2017 Jan 28.

Departments of Oncology and Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Limited information is available regarding neurocognitive outcomes of children who experience seizures during treatment for acute lymphoblastic leukemia (ALL). Accordingly, the main objectives of this study were to determine the incidence and risk factors for treatment-related seizures among children with ALL, and the neurocognitive outcomes associated with treatment-related seizures.

Procedure: Prospective neuropsychological assessment and magnetic resonance imaging (MRI) were planned for all 498 patients with newly diagnosed ALL enrolled on the St. Jude Total Therapy XV (TOTXV) protocol at three time points. The study database was reviewed retrospectively to identify those with treatment-related seizure. To assess neurocognitive changes associated with seizure, each patient with treatment-related seizure was matched with two cohort patients without seizure for age at treatment, gender, race, and treatment intensity.

Results: Nineteen patients developed seizure, with a 2-year cumulative risk of 3.82 ± 0.86% (SE). No risk factors were identified to be associated with the development of seizure, with a possible exception of intensive chemotherapy used on the standard/high-risk arm as compared to the low-risk arm. Neuropsychological performance of the seizure group, as compared to normative scores and nonseizure control cohort, indicated problems in attention, working memory, and processing speed. Cognitive deficits persisted 2 years after therapy, with additional declines in intellectual function observed. MRI indicated early neurotoxicity among the seizure group, as evidenced by greater leukoencephalopathy on initial examinations.

Conclusion: Treatment-related seizures were associated with leukoencephalopathy and decreased neuropsychological performance. Prospective studies are needed to detect changes in neurocognitive status associated with long-term functional impairment.
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http://dx.doi.org/10.1002/pbc.26436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469699PMC
August 2017

An infant with MLH3 variants, FOXG1-duplication and multiple, benign cranial and spinal tumors: A clinical exome sequencing study.

Genes Chromosomes Cancer 2016 Feb 6;55(2):131-42. Epub 2015 Nov 6.

Pathology and Laboratory Medicine, University of California at Los Angeles, David Geffen School of Medicine, Los Angeles, CA, 90095.

A 4-month-old male infant presented with severe developmental delay, cerebellar, brainstem, and cutaneous hemangiomas, bilateral tumors (vestibular, hypoglossal, cervical, and lumbar spinal), and few café-au-lait macules. Cerebellar and lumbar tumor biopsies revealed venous telangiectasia and intraneural perineuroma, respectively. Sequencing NF1, NF2, and RASA1 (blood), and NF2 and SMARCB1 (lumbar biopsy) was negative for pathogenic mutations. Clinical exome sequencing (CES), requested for tumor syndrome diagnosis, revealed two heterozygous missense variants, c.359T>C;p.Phe120Ser and c.3344G>A;p.Arg1115Gln, in MLH3 (NM_001040108.1), a DNA mismatch repair (MMR) gene, Polyphen-predicted as probably damaging, and benign, respectively. Sanger sequencing confirmed both variants in the proband, and their absence in the mother; biological father unavailable. Both biopsied tissues were negative for microsatellite instability, and expressed MLH1, MSH2, PMS2, MSH6, and MLH3 immunohistochemically. Chromosomal microarray showed a 133 kb segment copy number duplication of 14q12 region encompassing FOXG1, possibly explaining the developmental delay, but not the tumors. The presence of MLH3 variants with multiple benign neural and vascular tumors was intriguing for their possible role in the pathogenesis of these neoplasms, which were suspicious for, but not diagnostic of, constitutional MMR deficiency. However, functional assays of non-neoplastic patient-derived cells showed intact base-base MMR function. Also, no previous FOXG1-aberrant patient was reported with tumors. We now report a 3-year-old FOXG1-duplicated patient with a yet undescribed tumor syndrome with clinical features of neurofibromatosis types I and II, where several validation studies could not ascertain the significance of CES findings; further studies may elucidate precise mechanisms and diagnosis for clinical management, including tumor surveillance.
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http://dx.doi.org/10.1002/gcc.22319DOI Listing
February 2016

Attention and working memory abilities in children treated for acute lymphoblastic leukemia.

Cancer 2010 Oct;116(19):4638-45

Department of Behavioral Medicine, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

Background: To extend investigation beyond global cognitive measures prevalent in the literature, this study examined attention and working memory (WM) abilities of survivors of childhood acute lymphoblastic leukemia (ALL), the separate contributions of attention and WM to intelligence quotient (IQ), and their association with neuroimaging changes.

Methods: Ninety-seven children with ALL received risk-directed therapy based on presenting clinical and biological factors. During consolidation therapy, low-risk patients received half the dose of intravenous methotrexate that standard-risk/high-risk patients received, and fewer doses of triple intrathecal therapy. Patients were classified according to end of consolidation magnetic resonance imaging scans (normal or leukoencephalopathy), and continuous measures of white matter structure were computed. As part of the protocol study, children completed cognitive assessment 2 years later (completion of therapy), using Digit Span Forward (DSF) for attention and Digit Span Backward (DSB) for WM.

Results: For the total sample and the standard-/high-risk group, Total Digit Span (TDS), DSF, and DSB were impaired relative to norms (P<.05). In the low-risk group, only DSB was impaired (P<.0001). Across groups, a higher percentage of patients performed below the average range (scale score<7) on DSB (66%) compared with the DSF (14%) or TDS (18%). Regression analysis indicated that DSB predicted estimated IQ (P<.05), after accounting for DSF. Leukoencephalopathy was predictive of lower TDS (P<.05).

Conclusions: WM appears to be especially sensitive to treatment-related changes in ALL survivors, detecting difficulties potentially missed by global intelligence measures. These findings may facilitate the identification of vulnerable neural pathways and the development of targeted cognitive interventions.
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http://dx.doi.org/10.1002/cncr.25343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946517PMC
October 2010

Proximal dentatothalamocortical tract involvement in posterior fossa syndrome.

Brain 2009 Nov 5;132(Pt 11):3087-95. Epub 2009 Oct 5.

Department of Oncology, Division of Cancer Survivorship, St Jude Children's Research Hospital, 332 North Lauderdale St, Memphis, TN 38105, USA.

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.
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http://dx.doi.org/10.1093/brain/awp241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2781745PMC
November 2009

Passive range of motion functional magnetic resonance imaging localizing sensorimotor cortex in sedated children.

J Neurosurg Pediatr 2009 Oct;4(4):317-22

Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38104, USA.

Object: In this study, the authors examined whether passive range of motion (ROM) under conscious sedation could be used to localize sensorimotor cortex using functional MR (fMR) imaging in children as part of their presurgical evaluation.

Methods: After obtaining institutional review board approval (for retrospective analysis of imaging data acquired for clinical purposes) and informed consent, 16 children underwent fMR imaging. All 16 had lesions; masses were found in 9 patients and cortical dysplasia was found in 4; the lesions in 3 patients were not diagnosed. Passive ROM was performed during blood oxygen level-dependent MR imaging sequences. Three of the patients also performed active motor tasks during the fMR imaging study. All patients were evaluated using passive ROM of the hand and/or foot; 3 patients were evaluated for passive touch of the face. In 9 cases, intraoperative electrocorticography (ECoG) was used. Five of the patients underwent intraoperative ECoG to evaluate for seizure activity. Four patients had intraoperative ECoG for motor mapping. Five of the patients had subdural grids placed for extraoperative monitoring.

Results: In 3 cases, the active and passive ROMs colocalized. In 4 patients ECoG was used to identify motor cortex, and in all 4 motor ECoG yielded results consistent with the passive ROM localization. Thirteen of 16 children have undergone resection based on passive ROM fMR imaging findings with no unanticipated deficits.

Conclusions: These preliminary data suggest that passive ROM fMR imaging can accurately detect functional hand, leg, and face regions of the sensorimotor cortex in the sedated child. This extends current extraoperative mapping capabilities to patients unable or unwilling to cooperate for active motor tasks.
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http://dx.doi.org/10.3171/2009.4.PEDS08402DOI Listing
October 2009

Lack of correlation between the histologic and magnetic resonance imaging results of optic nerve involvement in eyes primarily enucleated for retinoblastoma.

Ophthalmology 2009 Aug 9;116(8):1558-63. Epub 2009 Jul 9.

Hamilton Eye Institute, Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.

Purpose: To correlate the histologic and magnetic resonance imaging results of the optic nerve in eyes primarily enucleated for retinoblastoma.

Design: Retrospective, clinicopathologic correlation.

Participants: Sixty-seven consecutive patients with retinoblastoma who underwent primary enucleation.

Methods: The histologic results of 67 eyes from 67 patients with retinoblastoma who underwent primary enucleation between March 1997 and January 2008 were studied for evidence of optic nerve invasion. Two neuroradiologists independently reviewed available preoperative magnetic resonance imaging studies with special emphasis on nonenhanced T2-weighted and gadolinium-enhanced T1-weighted imaging for evidence of optic nerve invasion. A weighted kappa statistic was used to assess agreement between observers.

Main Outcome Measures: Correlation between neuroradiologists and histologic results.

Results: Of the 67 eyes studied, 60 had preoperative magnetic resonance images, 58 of which were deemed appropriate for review by both neuroradiologists. Review of the histologic results showed optic nerve involvement in 62 (93%) of 67 eyes: 28 prelaminar (42%), 24 laminar (36%), and 10 postlaminar (15%). On review of the magnetic resonance scans, the first neuroradiologist identified optic nerve involvement in 57 (95%) of 60 eyes: 26 prelaminar (43%), 10 laminar (17%), and 11 postlaminar (18%). The second neuroradiologist identified optic nerve involvement in 46 (77%) of 60 eyes: 33 prelaminar (55%), 9 laminar (15%), and 4 postlaminar (7%). Moderate agreement existed between neuroradiologists (kappa, 0.55). Poor and fair agreement existed between each of the 2 neuroradiologists and histologic results, respectively (kappa, 0.29 and 0.17). Exophytic tumors showed the greatest disparity (kappa, -0.20 and -0.13) between magnetic resonance imaging and histologic results.

Conclusions: Limited correlation was found between magnetic resonance imaging and histologic results in assessing optic nerve invasion in eyes with retinoblastoma. Magnetic resonance imaging using routine imaging technologies, although useful in the evaluation of retinoblastoma, has limited usefulness in assessing the exact extent of optic nerve invasion; high-risk features of retinoblastoma such as postlaminar invasion remain best defined by histologic analysis. This study demonstrates that the interpretation of optic nerve involvement by a radiologist should not be the determining factor to defer enucleation in favor of neoadjuvant therapy.
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http://dx.doi.org/10.1016/j.ophtha.2009.02.018DOI Listing
August 2009

PET-CT of the normal spinal cord in children.

Acad Radiol 2009 Jul 8;16(7):881-5. Epub 2009 May 8.

Department of Radiological Sciences, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

Rationale And Objectives: The aim of this study was 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, the fluorodeoxyglucose activity in the pons and three cervical, three thoracic, and two lumbar spinal cord levels was subjectively graded as minimal, moderate, or intense. From regions of interest at each level, the maximum standardized uptake value was determined. Patients were grouped by age: group 1, <5 years; group 2, > or =5 to <10 years; group 3, > or =10 to <15 years; and group 4, > or =15 to <22 years. Subjective grade and standardized uptake values were compared at each level and for each level between age groups. The alpha level was set at 0.0046 on the basis of Bonferroni's 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 grades and standardized uptake values were higher in the pons, midcervical, and low thoracic areas than elsewhere in all age groups. Subjective grades significantly increased with age in the cervical and thoracic cord (P < .0005). Standardized uptake values in the pons and all cord levels significantly increased with increasing age (P < or = .0008).

Conclusions: In children, the metabolic activity of the spinal cord increases with age. On positron emission tomography, the cord can appear intensely avid in the midcervical and low thoracic areas.
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http://dx.doi.org/10.1016/j.acra.2009.01.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3680129PMC
July 2009

Phase I and pharmacokinetic studies of erlotinib administered concurrently with radiotherapy for children, adolescents, and young adults with high-grade glioma.

Clin Cancer Res 2009 Jan;15(2):701-7

Department of Oncology, St. Jude Children's Research Hospital, Mail Stop 260, 262 Danny Thomas Place, Memphis, TN 38105, USA.

Purpose: To estimate the maximum-tolerated dose (MTD) of erlotinib administered during and after radiotherapy, 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 200 mg/m(2) per day) were planned in this phase I study. Dose-limiting toxicities (DLT) were evaluated during first 8 weeks of therapy. Local radiotherapy (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 done in tumor tissue.

Results: Median age at diagnosis of 23 patients was 10.7 years (range, 3.7-22.5 years). MTD of erlotinib was 120 mg/m(2) per day. Skin rash and diarrhea were generally well controlled with supportive care. Dose-limiting toxicities were diarrhea (n = 1), increase in serum lipase (n = 1), and rash with pruritus (n = 1). The pharmacokinetic variables 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 120 mg/m(2) per day, pharmacokinetic studies showed wide interpatient variability in drug exposure.
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http://dx.doi.org/10.1158/1078-0432.CCR-08-1923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629527PMC
January 2009

Phase 1 study of an oxaliplatin and etoposide regimen in pediatric patients with recurrent solid tumors.

Cancer 2009 Feb;115(3):655-64

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

Background: The combination of a platinating agent and etoposide has induced responses in various pediatric tumors. The study estimated the maximum tolerated dose (MTD) of an oxaliplatin and etoposide regimen in children with recurrent solid tumors.

Methods: Oxaliplatin was administered on Day 1 and etoposide on Days 1 to 3 of each 21-day course. Cohorts of 3 to 6 patients were enrolled at 3 dose levels: 1) oxaliplatin at a dose of 130 mg/m(2) and etoposide at a dose of 75 mg/m(2), 2) oxaliplatin at a dose of 130 mg/m(2) and etoposide at a dose of 100 mg/m(2), and 3) oxaliplatin at a dose of 145 mg/m(2) and etoposide at a dose of 100 mg/m(2). Calcium and magnesium infusions were used at dose level 3 in an attempt to escalate the oxaliplatin dose past the single-agent MTD.

Results: The 16 patients received a total of 63 courses. At dose level 1, dose-limiting epistaxis, neuropathy, and neutropenia occurred in 1 of 6 patients. No dose-limiting toxicity (DLT) occurred at dose level 2 (n = 6). At dose level 3, 2 of 4 patients experienced dose-limiting neutropenia; none experienced grade 3 or 4 acute neuropathy. Six patients required prolongation of the oxaliplatin infusion because of acute sensory neuropathy. Responses were observed in patients with medulloblastoma (1 complete response) and pineoblastoma (1 partial response); 3 others with atypical teratoid rhabdoid tumor, ependymoma, and soft tissue sarcoma had prolonged disease stabilization.

Conclusions: The MTD of this regimen was found to be oxaliplatin at a dose of 130 mg/m(2) given on Day 1 and etoposide at a dose of 100 mg/m(2)/d given on Days 1 to 3. Neutropenia was found to be the DLT. Calcium and magnesium infusions did not allow escalation of the oxaliplatin dose. The combination was well-tolerated and demonstrated antitumor activity.
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http://dx.doi.org/10.1002/cncr.24054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2852396PMC
February 2009

Recurrent intrathecal methotrexate induced neurotoxicity in an adolescent with acute lymphoblastic leukemia: Serial clinical and radiologic findings.

Pediatr Blood Cancer 2009 Feb;52(2):293-5

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

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.
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http://dx.doi.org/10.1002/pbc.21764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2605174PMC
February 2009

Brain structural abnormalities in survivors of pediatric posterior fossa brain tumors: a voxel-based morphometry study using free-form deformation.

Neuroimage 2008 Aug 23;42(1):218-29. Epub 2008 Apr 23.

Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Voxel-based morphometry was used to compare brain structure of survivors of posterior fossa brain tumor (PFBT) with that of normal sibling controls to investigate disease- or cancer treatment-induced changes. Two different spatial normalization approaches that are available in public domain software (free-form deformation (FFD) and discrete cosine transform (DCT)) were compared for accuracy of normalization in the PFBT patients. Anatomical landmark matching demonstrated that spatial normalization was more accurate with FFD than with DCT. Voxel-based morphometry of the FFD-normalized magnetic resonance images from PFBT survivors and sibling controls detected reduced gray matter density in the thalamus and entorhinal cortex and reduced white matter density in the internal capsule, hypothalamus, corpus callosum, and cuneus of the occipital lobe in the PFBT survivors. Identification of these morphologic lesions may help localize the neural substrates of disease- or therapy-induced cognitive deficits in survivors of childhood cancer.
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http://dx.doi.org/10.1016/j.neuroimage.2008.04.181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2591023PMC
August 2008

Young age may predict a better outcome for children with diffuse pontine glioma.

Cancer 2008 Aug;113(3):566-72

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

Background: Because diffuse pontine glioma (DPG) is rare among young children, the outcome of affected patients is unknown.

Methods: The authors reviewed clinical and radiologic characteristics of all children aged <3 years with DPG who were evaluated at their institution. Inclusion followed standard magnetic resonance imaging criteria for the diagnosis of DPG.

Results: The median age at diagnosis in 10 patients was 2.2 years (range, 0.8-2.7 years). The median interval between the onset of symptoms and diagnosis was 2.5 months. All patients presented with cranial nerve palsy with (n = 7) or without (n = 3) other neurologic deficits attributable to brainstem involvement. All patients had pons-based tumors involving >50% of this brainstem segment. Histologic confirmation was attempted in 2 patients who had atypical radiologic features at diagnosis. Four patients initially were observed only. All patients received therapy, which consisted of radiation therapy (RT) (n = 2), RT and chemotherapy (n = 6), or chemotherapy only (n = 2). Four patients died of tumor progression after a median of 0.7 years (range, 0.5-3.7 years). Six patients have survived for a median of 2.3 years (range, 0.9-8 years). The 3-year progression-free and overall survival rates were 45% +/- 19% and 69% +/- 19%, respectively.

Conclusions: Children aged <3 years with DPG potentially may fare better than older patients with the same diagnosis despite the use of similar therapy. The current results suggested that DPG in younger children may be distinct biologically from similar tumors in older age groups.
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http://dx.doi.org/10.1002/cncr.23584DOI Listing
August 2008

High-dose chemotherapy with autologous stem cell rescue for children with recurrent malignant brain tumors.

Cancer 2008 Mar;112(6):1345-53

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Background: High-dose chemotherapy (HDCT) with autologous stem cell rescue (ASCR) has been reported to be effective in treating children with recurrent central nervous system (CNS) malignancies.

Methods: To evaluate the efficacy and toxicities of HDCT and ASCR, the medical records of 27 children with recurrent CNS malignancies who received such therapy at St. Jude Children's Research Hospital between 1989 and 2004 were reviewed.

Results: The median age at diagnosis was 4.5 years (range, 0.4-16.6 years) and that at ASCR was 6.7 years (range, 1.1-18.5 years). Diagnoses included medulloblastoma (13 patients), primitive neuroectodermal tumor (3 patients), pineoblastoma (2 patients), atypical teratoid rhabdoid tumor (2 patients), ependymoma (3 patients), anaplastic astrocytoma (2 patients), and glioblastoma multiforme (2 patients). The 5-year overall and progression-free survival (PFS) rates were 28.2% and 18.5%, respectively. The 5-year PFS rate for patients aged<3 years at diagnosis (57.1%) was significantly better than older patients (5.0%) (P=.019). Among the 6 long-term survivors (5 with M0 disease and 1 with M3 disease at diagnosis), 5 received both radiotherapy and HDCT as part of their salvage regimen; 4 were aged<3 years at diagnosis and had received chemotherapy only as part of frontline therapy. Two patients died of transplant-related toxicities; 44% experienced grade 3 or 4 transplant-related toxicities (toxicities were graded according to the National Cancer Institute Common Toxicity Criteria).

Conclusions: HDCT with ASCR is not an effective salvage strategy for older children with recurrent CNS malignancies. The significantly better outcome in the younger cohort was most likely related to the use of radiotherapy as part of the salvage strategy.
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http://dx.doi.org/10.1002/cncr.23305DOI Listing
March 2008

Vertebral body growth after craniospinal irradiation.

Int J Radiat Oncol Biol Phys 2008 Apr 31;70(5):1343-9. Epub 2007 Dec 31.

Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.

Purpose: To estimate the effects of radiotherapy and clinical factors on vertebral growth in patients with medulloblastoma and supratentorial primitive neuroectodermal tumors treated with craniospinal irradiation (CSI) and chemotherapy.

Methods And Materials: The height of eight individual or grouped vertebral bodies (C3, C3-C4, T4, T4-T5, C6-T3, T4-T7, L3, L1-L5) was measured before and after CSI (23.4 or 36-39.6 Gy) in 61 patients. Of the 61 patients, 40 were boys and 21 were girls (median age, 7 years; range, 3-13 years), treated between October 1996 and October 2003. Sagittal T(1)-weighted magnetic resonance images were used for the craniocaudal measurements. The measurements numbered 275 (median, 5/patient; range, 3-7). The median follow-up after CSI was 44.1 months (range, 13.8-74.9 months).

Results: Significant growth was observed in all measured vertebrae. Excluding C3-C4, the growth rate of the grouped vertebrae was affected by age, gender, and CSI dose (risk classification). The risk classification alone affected the growth rates of C3 (p = 0.002) and L3 (p = 0.02). Before CSI, the length of all vertebral bodies was an increasing function of age (p <0.0001). The C3 length before CSI was affected by gender and risk classification: C3 was longer for female (p = 0.07) and high-risk (p = 0.07) patients.

Conclusion: All vertebrae grew significantly after CSI, with the vertebrae of the boys and younger patients growing at a rate greater than that of their counterparts. The effect of age was similar across all vertebrae, and gender had the greatest effect on the growth of the lower cervical and upper thoracic vertebrae. The effect of the risk classification was greatest in the lumbar spine by a factor of < or = 10.
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http://dx.doi.org/10.1016/j.ijrobp.2007.08.085DOI Listing
April 2008

Phase I study of everolimus in pediatric patients with refractory solid tumors.

J Clin Oncol 2007 Oct;25(30):4806-12

Department of Oncology, St Jude Children's Research Hospital, Memphis, TN 38105-2794, USA.

Purpose: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic and pharmacodynamic properties of the mammalian target of rapamycin (mTOR) inhibitor, everolimus, in children with refractory or recurrent solid tumors.

Patients And Methods: Everolimus was administered orally at a daily dose of 2.1, 3, 5, or 6.5 mg/m2 in cohorts of three to six patients per dosage level. Pharmacokinetic and pharmacodynamic studies were performed during the first course. The phosphorylation status of various components of the mTOR signal pathway was assessed in peripheral-blood mononuclear cells (PBMCs) isolated from treated patients.

Results: There were 26 patients enrolled; 18 were assessable. DLTs included diarrhea (n = 1), mucositis (n = 1), and elevation of ALT (n = 1) at 6.5 mg/m2. At the MTD of 5 mg/m2, the median everolimus clearance was 15.2 L/h/m2, with a plasma everolimus concentration-time area under the curve (AUC) from 0 to infinity of 239.6 ng/mL x h. Significant inhibition of mTOR pathway signaling was observed in PBMCs from patients achieving AUCs 200 ng/mL x h, equivalent to dosages of 3 to 5 mg/m2 of everolimus. No objective tumor responses were observed.

Conclusion: Continuous, orally administered everolimus is well tolerated in children with recurrent or refractory solid tumors and demonstrates similar pharmacokinetic properties to those observed in adults. Everolimus significantly inhibits the mTOR signaling pathway in children at the MTD. The recommended phase II dose in children with solid tumors is 5 mg/m2.
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http://dx.doi.org/10.1200/JCO.2007.11.4017DOI Listing
October 2007

A phase II study of the farnesyl transferase inhibitor, tipifarnib, in children with recurrent or progressive high-grade glioma, medulloblastoma/primitive neuroectodermal tumor, or brainstem glioma: a Children's Oncology Group study.

Cancer 2007 Dec;110(11):2535-41

Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA.

Background: An open-label Phase II study of tipifarnib was conducted to evaluate its safety and efficacy in children with recurrent or refractory medulloblastoma (MB)/primitive neuroectodermal tumor (PNET), high-grade glioma (HGG), and diffuse intrinsic brainstem glioma (BSG).

Methods: Between January 2004 and July 2005, patients were enrolled and stratified as follows: Stratum 1, recurrent or refractory MB/PNET; Stratum 2, recurrent or refractory HGG; and Stratum 3, recurrent or refractory BSG. Patients received tipifarnib 200 mg/m2 per dose twice daily for 21 days repeated every 28 days. Patients who received enzyme-inducing anticonvulsants and other CYP3A4/5 inducers or inhibitors were excluded. The primary objective was to estimate the sustained response rate in all strata.

Results: Ninety-seven patients with a median age of 11.2 years (range, 3.2-21.9 years) were enrolled on the study, and 81 patients were evaluable for response. One of 35 patients with BSG and 1 of 31 patients with HGG had a sustained partial response. No responses were observed in 15 patients with MB/PNET. Eight patients (3 HGG, 1 MB, and 4 BSG) remained stable for >or=4 courses (range, 4-25 courses). The median number of courses received was 2 (range, 1-25 courses). The most frequent grade 3 and 4 toxicities included neutropenia (18.7%), thrombocytopenia (14.3%), and leukopenia (14.3%). The 6-month progression-free survival rate (+/-standard deviation) was 14%+/-6% for HGG, 6%+/-6% for MB/PNET and 3%+/-3% for BSG.

Conclusions: Tipifarnib tolerated well but had little activity as a single agent in children with recurrent central nervous system malignancies.
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http://dx.doi.org/10.1002/cncr.23078DOI Listing
December 2007

Childhood central nervous system leukemia: historical perspectives, current therapy, and acute neurological sequelae.

Neuroradiology 2007 Nov 9;49(11):873-88. Epub 2007 Oct 9.

Division of Diagnostic Imaging (MS #210), Department of Radiological Sciences, St. Jude Children's Research Hospital, 332 N. Lauderdale Street, Memphis, TN, 38105-2794, USA.

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.
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http://dx.doi.org/10.1007/s00234-007-0300-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2386669PMC
November 2007

Quantitative morphologic evaluation of magnetic resonance imaging during and after treatment of childhood leukemia.

Neuroradiology 2007 Nov 26;49(11):889-904. Epub 2007 Jul 26.

Division of Translational Imaging Research (MS #210), Department of Radiological Sciences, St. Jude Children's Research Hospital, 332 N. Lauderdale Street, Memphis, TN, 38105-2794, USA.

Introduction: Medical advances over the last several decades, including CNS prophylaxis, have greatly increased survival in children with leukemia. As survival rates have increased, clinicians and scientists have been afforded the opportunity to further develop treatments to improve the quality of life of survivors by minimizing the long-term adverse effects. When evaluating the effect of antileukemia therapy on the developing brain, magnetic resonance (MR) imaging has been the preferred modality because it quantifies morphologic changes objectively and noninvasively.

Method And Results: Computer-aided detection of changes on neuroimages enables us to objectively differentiate leukoencephalopathy from normal maturation of the developing brain. Quantitative tissue segmentation algorithms and relaxometry measures have been used to determine the prevalence, extent, and intensity of white matter changes that occur during therapy. More recently, diffusion tensor imaging has been used to quantify microstructural changes in the integrity of the white matter fiber tracts. MR perfusion imaging can be used to noninvasively monitor vascular changes during therapy. Changes in quantitative MR measures have been associated, to some degree, with changes in neurocognitive function during and after treatment.

Conclusion: In this review, we present recent advances in quantitative evaluation of MR imaging and discuss how these methods hold the promise to further elucidate the pathophysiologic effects of treatment for childhood leukemia.
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http://dx.doi.org/10.1007/s00234-007-0262-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2386666PMC
November 2007

A digital pediatric brain structure atlas from T1-weighted MR images.

Med Image Comput Comput Assist Interv 2006 ;9(Pt 2):332-9

Division of Translational Imaging Research, Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

Human brain atlases are indispensable tools in model-based segmentation and quantitative analysis of brain structures. However, adult brain atlases do not adequately represent the normal maturational patterns of the pediatric brain, and the use of an adult model in pediatric studies may introduce substantial bias. Therefore, we proposed to develop a digital atlas of the pediatric human brain in this study. The atlas was constructed from T1-weighted MR data set of a 9-year old, right-handed girl. Furthermore, we extracted and simplified boundary surfaces of 25 manually defined brain structures (cortical and subcortical) based on surface curvature. We constructed a 3D triangular mesh model for each structure by triangulation of the structure's reference points. Kappa statistics (cortical, 0.97; subcortical, 0.91) indicated substantial similarities between the mesh-defined and the original volumes. Our brain atlas and structural mesh models (www.stjude.org/brainatlas) can be used to plan treatment, to conduct knowledge and model-driven segmentation, and to analyze the shapes of brain structures in pediatric patients.
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http://dx.doi.org/10.1007/11866763_41DOI Listing
April 2007

Safety in pediatric MR and cardiac CT: results of a membership survey of the Society for Pediatric Radiology-2006.

Pediatr Radiol 2007 Apr 27;37(4):409-12. Epub 2007 Feb 27.

Department of Radiological Sciences, St. Jude Children's Research Hospital, 332 N. Lauderdale, MS 752, Memphis, TN 38105-2794, USA.

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http://dx.doi.org/10.1007/s00247-007-0430-4DOI Listing
April 2007

Computer-aided detection of therapy-induced leukoencephalopathy in pediatric acute lymphoblastic leukemia patients treated with intravenous high-dose methotrexate.

Magn Reson Imaging 2006 Jul 27;24(6):785-91. Epub 2006 Apr 27.

Division of Translational Imaging Research, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

The purpose of this study was to use objective quantitative magnetic resonance imaging (MRI) methods to develop a computer-aided detection (CAD) tool to differentiate white matter (WM) hyperintensities into either leukoencephalopathy (LE) induced by chemotherapy or normal maturational processes in children treated for acute lymphoblastic leukemia without irradiation. A combined MRI set consisting of T1-weighted, T2-weighted, proton-density-weighted and fluid-attenuated inversion recovery images and WM, gray matter and cerebrospinal fluid proportional volume maps from a spatially normalized atlas were analyzed with a neural network segmentation based on a Kohonen self-organizing map (SOM). Segmented maps were manually classified to identify the most hyperintense WM region and the normal-appearing genu region. Signal intensity differences normalized to the genu within each examination were generated for four time points in 228 children. A second Kohonen SOM was trained on the first examination data and divided the WM into normal-appearing or LE groups. Reviewing labels from the CAD tool revealed a consistency measure of 89.8% (167 of 186) within patients. The overall agreement between the CAD tool and the consensus reading of two trained observers was 84.1% (535 of 636), with 84.2% (170 of 202) agreement in the training set and 84.1% (365 of 434) agreement in the testing set. These results suggest that subtle therapy-induced LE can be objectively and reproducibly detected in children treated for cancer using this CAD approach based on relative differences in quantitative signal intensity measures normalized within each examination.
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http://dx.doi.org/10.1016/j.mri.2006.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2396783PMC
July 2006

Hematometrocolpos in an adolescent female treated for pelvic Ewing sarcoma.

Pediatr Blood Cancer 2008 Jan;50(1):157-60

Department of Hematology/Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Radiation therapy is often used to achieve local control of pelvic Ewing sarcoma in children. The effects of radiation on the female reproductive tract have been well documented in adults with gynecological malignancies, but the long-term consequences of pelvic radiation in pre-pubertal or adolescent girls are not as well described. We report a case of hematometrocolpos developing in an adolescent previously treated with chemotherapy and radiation therapy for pelvic Ewing sarcoma. We describe the clinical presentation, radiographic features, gross pathology, treatment strategies, outcome, as well as putative predisposing factors and preventative interventions.
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http://dx.doi.org/10.1002/pbc.20833DOI Listing
January 2008

Advances toward an understanding of brainstem gliomas.

J Clin Oncol 2006 Mar;24(8):1266-72

Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.

The diagnosis of brainstem glioma was long considered a single entity. However, since the advent of magnetic resonance imaging in the late 1980s, neoplasms within this anatomic region are now recognized to include several tumors of varying behavior and natural history. More recent reports of brainstem tumors include diverse sites such as the cervicomedullary junction, pons, midbrain, or the tectum. Today, these tumors are broadly categorized as either diffuse intrinsic gliomas, most often in the pons, or the nondiffuse brainstem tumors originating at the tectum, focally in the midbrain, dorsal and exophytic to the brainstem, or within the cervicomedullary junction. Although we briefly discuss the nondiffuse tumors, we focus specifically on those diffuse brainstem tumors that regrettably still carry a bleak prognosis.
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http://dx.doi.org/10.1200/JCO.2005.04.6599DOI Listing
March 2006

Intratumoral hemorrhage among children with newly diagnosed, diffuse brainstem glioma.

Cancer 2006 Mar;106(6):1364-71

Department of Hematology-Oncology, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105, USA.

Background: Children with diffuse brainstem glioma (BSG) commonly undergo novel therapies because their outcome is poor with radiation therapy (RT). Although recent clinical trials using new biologic agents documented intratumoral hemorrhage (IH) among several children with BSG, to the authors' knowledge little is known regarding this phenomenon. In the current study, the authors assessed the characteristics and estimated the cumulative incidence of IH among children with BSG.

Methods: All available brain imaging studies and medical records of 48 consecutive patients with newly diagnosed BSG treated at the study institution over a 10-year interval (1992-2002) were reviewed. Treatment was comprised of RT and various regimens of conventional chemotherapy; none of these patients received biologic agents. At the time of last follow-up, all patients had died of tumor progression.

Results: The authors reviewed 319 imaging studies (251 magnetic resonance imaging scans and 68 computed tomography scans). IH was present in 6.25% of patients at the time of diagnosis. The 6-month and 12-month cumulative incidence estimates of IH regardless of the associated symptoms were 15.5% +/- 5.5% and 24.4% +/- 6.5%, respectively. The same estimates for symptomatic cases were 8.9% +/- 4% and 17.8% +/- 6%, respectively. All cases of IH at the time of diagnosis and 78% of symptomatic cases that developed after diagnosis were located in necrotic areas.

Conclusions: Although IH is uncommon at the time of diagnosis, symptomatic IH may occur among nearly 20% of children after the diagnosis of BSG. The uniform occurrence of IH among patients treated with various chemotherapeutic regimens and its association with necrotic areas suggests that tumor biology plays a significant role in this event.
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http://dx.doi.org/10.1002/cncr.21749DOI Listing
March 2006

Posterior reversible encephalopathy syndrome in children with cancer.

Pediatr Blood Cancer 2007 Feb;48(2):152-9

Division of Neurology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

Purpose: To identify predisposing factors, radiologic features, and clinical outcome of posterior reversible leucoencephalopathy (PRES) in children receiving cancer treatment.

Methods: We identified 11 patients (7 female) who had radiological and clinical features consistent with PRES and were treated for cancer at St. Jude Children's Research Hospital between January 1995 and January 2005. Clinical and radiographic data were abstracted from their records.

Results: The average age at the time of PRES onset was 10.4 years. Primary diagnoses were acute leukemia (n = 8), non-Hodgkin lymphoma (n = 2), and Ewing sarcoma (n = 1). PRES occurred in 8 patients during the induction phase of treatment, and all 11 patients had hypertension (5 chronically). Seizure activity was proximate to cytarabine and tacrolimus administration in three patients and further seizures occurred with re-administration of these medications in two patients. Coagulation and chemistry studies were normal. Concurrent brain magnetic resonance imaging (MRI) demonstrated T2 signal abnormalities in all 11 patients, restricted diffusion in 4, and hemorrhage in 3. Follow-up MRI showed chronic changes consistent with a previous hemorrhage in three and evidence of prior parenchymal ischemia in one. Three patients developed epilepsy and remain on chronic anticonvulsant therapy.

Conclusions: PRES is an increasingly recognized complication of pediatric cancer treatment. Risk factors for PRES in pediatric cancer patients include hypertension (not necessarily acute), remission induction chemotherapy, and administration of tacrolimus. MR images often show atypical findings, some of which are irreversible. A significant number of patients develop epilepsy despite clinical and radiographic evidence of recovery.
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http://dx.doi.org/10.1002/pbc.20703DOI Listing
February 2007