Publications by authors named "Kathleen Helton"

54 Publications

Developmental patterns of CBF and BOLD responses to visual stimulus.

J Cereb Blood Flow Metab 2021 Mar 21;41(3):630-640. Epub 2020 May 21.

Departments of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, TN, USA.

To investigate the developmental changes of cerebral blood flow (CBF) and hemodynamic responses to changing neural activity, we used the arterial spin label (ASL) technique to measure resting CBF and simultaneous CBF / blood-oxygen-level dependent (BOLD) signal changes during visual stimulation in 97 typically developing children and young adults (age 13.35 [6.02, 25.25] (median [min, max]) years old at the first time point). The longitudinal study protocol included three MRIs (2.7 ± 0.06 obtained), one year apart, for each participant. Mixed-effect linear and non-linear statistical models were used to analyze age effects on CBF and BOLD signals. Resting CBF decreased exponentially with age ( = 0.0001) throughout the brain, and developmental trajectories differed across brain lobes. The absolute CBF increase in visual cortex during stimulation was constant over the age range, but the fractional CBF change increased with age ( = 0.0001) and the fractional BOLD signal increased with age ( = 0.0001) correspondingly. These findings suggest that the apparent neural hemodynamic coupling in visual cortex does not change after age six years, but age-related BOLD signal changes continue through adolescence primarily due to the changes with age in resting CBF.
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http://dx.doi.org/10.1177/0271678X20925303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922748PMC
March 2021

Removal of Arterial Vessel Contributions in Susceptibility-Weighted Images for Quantification of Normalized Visible Venous Volume in Children with Sickle Cell Disease

J Healthc Eng 2017 ;2017

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

Purpose: To evaluate a new postprocessing framework that eliminates arterial vessel signal contributions in the quantification of normalized visible venous volume (NVVV, a ratio between venous and brain volume) in susceptibility-weighted imaging (SWI) exams in patients with sickle cell disease (SCD).

Materials And Methods: We conducted a retrospective study and qualitatively reviewed for hypointense arterial vessel contamination in SWI exams from 21 children with SCD. We developed a postprocessing framework using magnetic resonance angiography in combination with SWI to provide a more accurate quantification of NVVV. NVVV was calculated before and after removing arterial vessel contributions to determine the error from hypointense arterial vessels in quantifying NVVV.

Results: Hypointense arterial vessel contamination was observed in 86% SWI exams and was successfully corrected by the proposed method. The contributions of hypointense arterial vessels in the original SWI were significant and accounted for approximately 33% of the NVVV [uncorrected NVVV = 0.012 ± 0.005 versus corrected NVVV = 0.008 ± 0.003 (mean ± SD), P < 0.01].

Conclusion: Hypointense arterial vessel contamination occurred in the majority of SWI exams and led to a sizeable overestimation of the visible venous volume. A prospective longitudinal study is needed to evaluate if quantitation of NVVV was improved and to assess the role of NVVV as a biomarker of SCD severity or stroke risk.
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http://dx.doi.org/10.1155/2017/5369385DOI Listing
January 2017

Removal of Arterial Vessel Contributions in Susceptibility-Weighted Images for Quantification of Normalized Visible Venous Volume in Children with Sickle Cell Disease.

J Healthc Eng 2017 28;2017:5369385. Epub 2017 Aug 28.

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

Purpose: To evaluate a new postprocessing framework that eliminates arterial vessel signal contributions in the quantification of normalized visible venous volume (NVVV, a ratio between venous and brain volume) in susceptibility-weighted imaging (SWI) exams in patients with sickle cell disease (SCD).

Materials And Methods: We conducted a retrospective study and qualitatively reviewed for hypointense arterial vessel contamination in SWI exams from 21 children with SCD. We developed a postprocessing framework using magnetic resonance angiography in combination with SWI to provide a more accurate quantification of NVVV. NVVV was calculated before and after removing arterial vessel contributions to determine the error from hypointense arterial vessels in quantifying NVVV.

Results: Hypointense arterial vessel contamination was observed in 86% SWI exams and was successfully corrected by the proposed method. The contributions of hypointense arterial vessels in the original SWI were significant and accounted for approximately 33% of the NVVV [uncorrected NVVV = 0.012 ± 0.005 versus corrected NVVV = 0.008 ± 0.003 (mean ± SD), < 0.01].

Conclusion: Hypointense arterial vessel contamination occurred in the majority of SWI exams and led to a sizeable overestimation of the visible venous volume. A prospective longitudinal study is needed to evaluate if quantitation of NVVV was improved and to assess the role of NVVV as a biomarker of SCD severity or stroke risk.
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http://dx.doi.org/10.1155/2017/5369385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5592388PMC
July 2019

The Complex Diagnostic Challenge in Children With Non-Central Nervous System Cancer and Cerebellar Mutism.

J Child Neurol 2017 08 12;32(9):823-827. Epub 2017 May 12.

3 Department of Neurology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Multiple etiologies should be considered in the differential diagnosis of immunocompromised patients with non-central nervous system cancer and viral infections who develop mutism. Acute cerebellitis, caused by infections or by neurotoxicity resulting from chemotherapy; paraneoplastic cerebellar degeneration; atypical posterior reversible encephalopathy syndrome; and acute disseminated encephalomyelitis may all cause mutism in such patients. This condition warrants prompt recognition and may require treatment with immunotherapy, as it may be an immune-mediated process. We present 2 patients with leukemia and viral illness who developed cerebellar mutism in the setting of acute cerebellitis and responded to immunotherapy, suggesting that the condition involved a parainfectious immune-mediated response.
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http://dx.doi.org/10.1177/0883073817709178DOI Listing
August 2017

Imaging in viral infections of the central nervous system: can images speak for an acutely ill brain?

Emerg Radiol 2017 Jun 16;24(3):287-300. Epub 2016 Nov 16.

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

Viral infections involving the central nervous system (CNS) may result from a wide variety of agents and have clinically overlapping manifestations. The diagnosis is often made based on a combination of the clinical exam, local epidemiology, imaging, and biochemical findings. Despite the advances in medicine and imaging, the diagnosis often remains elusive. Imaging, however, still plays a vital role in suggesting the diagnosis in typical cases, excluding potential mimics, and in evaluating changes with therapy. Herein, the authors present a review of various common and rare viral encephalitides with emphasis on the imaging literature.
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http://dx.doi.org/10.1007/s10140-016-1463-5DOI Listing
June 2017

Hydroxycarbamide treatment and brain MRI/MRA findings in children with sickle cell anaemia.

Br J Haematol 2016 Oct 8;175(2):331-338. Epub 2016 Sep 8.

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

Silent cerebral infarction (SCI) is the most common neurological abnormality among children with sickle cell anaemia (SCA). The effect of hydroxycarbamide (also termed hydroxyurea) on the development and progression of SCI is unclear. We evaluated brain magnetic resonance imaging/angiography (MRI/MRA) in children with SCA receiving long-term hydroxycarbamide therapy. Fifty participants (median 9·4 years, range 1·1-17·3) enrolled in the Hydroxyurea Study of Long-Term Effects (HUSTLE; NCT00305175) underwent brain MRI/MRA and laboratory evaluations before hydroxycarbamide initiation and after 3 and 6 years of treatment to maximum tolerated dose. SCI and vascular stenosis were evaluated. At baseline, 3 and 6 years, SCI were present in 19/50 (38%), 20/49 (41%), and 7/17 (41%), respectively. At 3 years, one child developed a SCI lesion, and another progressed (single lesion to multiple). Lower haemoglobin (Hb) (80 g/l vs. 86 g/l, P = 0·049), fetal Hb (5·0% vs. 10·4%, P < 0·001) and oxygen saturation (97% vs. 98%, P = 0·027) before hydroxycarbamide initiation were associated with SCI. No patients had vascular stenosis identified on MRA, transient ischaemic attack or stroke. Our data indicate that children receiving hydroxycarbamide over a 3- to 6-year period have a low rate of new or worsening cerebrovascular disease. Further studies are needed to confirm that hydroxycarbamide can prevent the onset and progression of SCI.
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http://dx.doi.org/10.1111/bjh.14235DOI Listing
October 2016

Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial.

Lancet 2016 Feb 6;387(10019):661-70. Epub 2015 Dec 6.

Medical University of South Carolina, Charleston, SC, USA.

Background: For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions.

Methods: TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307.

Findings: Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (135-142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10-8·98). Non-inferiority (p=8·82 × 10(-16)) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions).

Interpretation: For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke.

Funding: National Heart, Lung, and Blood Institute, National Institutes of Health.
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http://dx.doi.org/10.1016/S0140-6736(15)01041-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5724392PMC
February 2016

Spatiotemporal Patterns of Tumor Occurrence in Children with Intraocular Retinoblastoma.

PLoS One 2015 31;10(7):e0132932. Epub 2015 Jul 31.

Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.

Purpose: To accurately map the retinal area covered by tumor in a prospectively enrolled cohort of children diagnosed with retinoblastoma.

Methods: Orbital MRI in 106 consecutive retinoblastoma patients (44 bilateral) was analyzed. For MRI-visible tumors, the polar angle and angle of eccentricity of points defining tumor perimeter on the retina were determined by triangulation from images in three orthogonal planes. The centroid of the mapped area was calculated to approximate tumor origin, and the location and cumulative tumor burden were analyzed in relation to mutation type (germline vs. somatic), tumor area, and patient age at diagnosis. Location of small tumors undetected by MRI was approximated with fundoscopic images.

Results: Mapping was successful for 129 tumors in 91 eyes from 67 patients (39 bilateral, 43 germline mutation). Cumulative tumor burden was highest within the macula and posterior pole and was asymmetrically higher within the inferonasal periphery. Tumor incidence was lowest in the superotemporal periphery. Tumor location varied with age at diagnosis in a complex pattern. Tumor location was concentrated in the macula and superonasal periphery in patients <5.6 months, in the inferotemporal quadrant of the posterior pole in patients 5.6-8.8 months, in the inferonasal quadrant in patients 8.8-13.2 months, and in the nasal and superotemporal periphery in patients >13.2 months. The distribution of MRI-invisible tumors was consistent with the asymmetry of mapped tumors.

Conclusions: MRI-based mapping revealed a previously unrecognized pattern of retinoblastoma localization that evolves with age at diagnosis. The structured spatiotemporal distribution of tumors may provide valuable clues about cellular or molecular events associated with tumorigenesis in the developing retina.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132932PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521796PMC
May 2016

Silent cerebral infarcts in very young children with sickle cell anaemia are associated with a higher risk of stroke.

Br J Haematol 2015 Oct 7;171(1):120-9. Epub 2015 Jun 7.

Departments of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Silent cerebral infarctions (SCI) are the most common neurological injury in children with sickle cell anaemia (SCA), but their incidence/prognosis in early childhood has not been well described. We report clinical, neuroradiological, psychometric and academic follow-up over an average period of 14 years in 37 children with SCA who had magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) of the brain between ages 7 and 48 months. Ten patients (27%) younger than age 5 years (Group I) had SCI, as did 12 (32%) older than 5 years (Group II). Fifteen (41%) had no lesions (Group III). Overt stroke or transient ischaemic attack occurred in 5/9 (56%) in Group I. Most Group I patients had progressive MRI abnormalities, concurrent stenosis, decreased cognitive ability, attention/executive function deficits and hindered academic attainment. The proportions of subjects in Group I with subsequent neurological events (P ≤ 0·006), progressive ischaemia (P ≤ 0·001) and vascular stenosis (P ≤ 0·006) were greater than in Groups II and III. Thus, SCI in young children with SCA may predict overt central nervous system events, progressive MRI abnormalities, stenosis, cognitive dysfunction and poor academic performance. Children younger than 5 years may benefit from MRI/MRA testing and should be considered for aggressive intervention when SCI are detected.
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http://dx.doi.org/10.1111/bjh.13525DOI Listing
October 2015

Comparing segmented ASL perfusion of vascular territories using manual versus semiautomated techniques in children with sickle cell anemia.

J Magn Reson Imaging 2015 Feb 8;41(2):439-46. Epub 2014 Jan 8.

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

Purpose: Elevated cerebral blood flow (CBF) in sickle cell anemia (SCA) is an adaptive pathophysiologic response associated with decreased vascular reserve and increased risk for ischemia. We compared manual (M) and semiautomated (SA) vascular territory delineation to facilitate standardized evaluation of CBF in children with SCA.

Materials And Methods: ASL perfusion values from 21 children were compared for gray matter and white matter (WM) in vascular territories defined by M and SA delineation. SA delineated CBF was compared with clinical and hematologic variables acquired within 4 weeks of the MRI.

Results: CBF measurements from M (MCA 82 left, 79 right) and SA (MCA 81 left, 81 right) delineated territories were highly correlated (R = 0.99, P < 0.0001). Bland-Altman plots had close-fitting limits of agreement of -1.8 to -3.5 lower limit and 0 to 1.8 upper limit. SA vascular territory delineation was comparable to the expert delineation with a kappa index of 0.62-0.85 and was considerably faster. Median territorial CBF values did not differ by gender or age. WM perfusion in the posterior cerebral artery territories was positively correlated with degree of hemolysis (R = 0.58, P = 0.01 left, 0.73, P < 0.001 right) and negatively correlated with hemoglobin (R = -0.48; P = 0.03 left; -0.47; P = 0.04 right) and hemoglobin F (R = -0.42; P = .09 left; -0.47; P = 0.049 right).

Conclusion: We established the validity of the SA method, which in our experience was much faster than the M method for delineation of vascular territories. Associations between CBF and hematologic variables may demonstrate pathophysiologic changes that contribute to clinical variation in CBF.
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http://dx.doi.org/10.1002/jmri.24559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4528912PMC
February 2015

Magnetic resonance imaging/angiography and transcranial Doppler velocities in sickle cell anemia: results from the SWiTCH trial.

Blood 2014 Aug 9;124(6):891-8. Epub 2014 Jun 9.

Cincinnati Children's Hospital, Cincinnati, OH.

The Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial compared standard (transfusions/chelation) to alternative (hydroxyurea/phlebotomy) treatment to prevent recurrent stroke and manage iron overload in children chronically transfused over 7 years before enrollment. Standardized brain magnetic resonance imaging/magnetic resonance angiography (MRA) and transcranial Doppler (TCD) exams were performed at entry and exit, with a central blinded review. A novel MRA vasculopathy grading scale demonstrated frequent severe baseline left/right vessel stenosis (53%/41% ≥Grade 4); 31% had no vessel stenosis on either side. Baseline parenchymal injury was prevalent (85%/79% subcortical, 53%/37% cortical, 50%/35% subcortical and cortical). Most children had low or uninterpretable baseline middle cerebral artery TCD velocities, which were associated with worse stenoses (incidence risk ratio [IRR] = 5.1, P ≤ .0001 and IRR = 4.1, P < .0001) than normal velocities; only 2% to 12% had any conditional/abnormal velocity. Patients with adjudicated stroke (7) and transient ischemic attacks (19 in 11 standard/8 alternative arm subjects) had substantial parenchymal injury/vessel stenosis. At exit, 1 child (alternative arm) had a new silent infarct, and another had worse stenosis. SWiTCH neuroimaging data document severe parenchymal and vascular abnormalities in children with SCA and stroke and support concerns about chronic transfusions lacking effectiveness for preventing progressive cerebrovascular injury. The novel SWiTCH vasculopathy grading scale warrants validation testing and consideration for use in future clinical trials. This trial was registered at www.clinicaltrials.gov as #NCT00122980.
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http://dx.doi.org/10.1182/blood-2013-12-545186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126329PMC
August 2014

In reply.

J Pediatr Hematol Oncol 2014 Aug;36(6):501-2

*Department of Neurology, University at Buffalo School of Medicine §Department of Pediatrics, Roswell Park Cancer Institute, Buffalo, NY †Department of Pediatrics, University of Miami Miller School of Medicine and Holtz Children's Hospital, Miami, FL ‡Department of Radiological Sciences St Jude Children's Research Hospital Memphis, TN ∥Department of Pediatrics, Georgia Health Science Center, Augusta, GA ¶Department of Pediatrics, West Virginia University Health Science Center Charleston, WV.

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http://dx.doi.org/10.1097/MPH.0000000000000145DOI Listing
August 2014

Neurocognitive and neuroradiologic central nervous system late effects in children treated on Pediatric Oncology Group (POG) P9605 (standard risk) and P9201 (lesser risk) acute lymphoblastic leukemia protocols (ACCL0131): a methotrexate consequence? A report from the Children's Oncology Group.

J Pediatr Hematol Oncol 2014 Jan;36(1):8-15

*Department of Neurology, University at Buffalo School of Medicine ∥Department of Pediatrics, Roswell Park Cancer Institute, Buffalo, NY †Department of Pediatrics, University of Miami Miller School of Medicine and Holtz Children's Hospital, Miami, FL ‡Statistics and Data Center, Children's Oncology Group, Monrovia, CA §Department of Radiological Sciences, St Jude Children's Research Hospital, Memphis, TN ¶Department of Pediatrics, Georgia Health Science Center, Augusta, GA #Department of Pediatrics, West Virginia University Health Science Center, Charleston, WV.

Concerns about long-term methotrexate (MTX) neurotoxicity in the 1990s led to modifications in intrathecal (IT) therapy, leucovorin rescue, and frequency of systemic MTX administration in children with acute lymphoblastic leukemia. In this study, neurocognitive outcomes and neuroradiologic evidence of leukoencephalopathy were compared in children treated with intense central nervous system (CNS)-directed therapy (P9605) versus those receiving fewer CNS-directed treatment days during intensive consolidation (P9201). A total of 66 children from 16 Pediatric Oncology Group institutions with "standard-risk" acute lymphoblastic leukemia, 1.00 to 9.99 years at diagnosis, without evidence of CNS leukemia at diagnosis were enrolled on ACCL0131: 28 from P9201 and 38 from P9605. Magnetic resonance imaging scans and standard neuropsychological tests were performed ≥2.6 years after the end of treatment. Significantly more P9605 patients developed leukoencephalopathy compared with P9201 patients (68%, 95% confidence interval 49%-83% vs. 22%, 95% confidence interval 5%-44%; P=0.001) identified as late as 7.7 years after the end of treatment. Overall, 40% of patients scored <85 on either Verbal or Performance IQ. Children on both studies had significant attention problems, but P9605 children scored below average on more neurocognitive measures than those treated on P9201 (82%, 14/17 measures vs. 24%, 4/17 measures). This supports ongoing concerns about intensive MTX exposure as a major contributor to CNS late effects.
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http://dx.doi.org/10.1097/MPH.0000000000000000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465396PMC
January 2014

Imaging features of medulloepithelioma: report of four cases and review of the literature.

Pediatr Radiol 2013 Oct 30;43(10):1344-56. Epub 2013 Aug 30.

Department of Radiological Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 220, Memphis, TN, 38105-3678, USA.

Background: Intraocular medulloepithelioma is a childhood tumor arising from the nonpigmented primitive ciliary neuroepithelium. Although rarer than retinoblastoma, it remains the second most common primary intraocular neoplasm in children. The rarity of intraocular medulloepithelioma creates the challenge in establishing a clinical diagnosis, and radiologically the tumor is often confused with other intraocular masses.

Objective: To describe the clinical, imaging and pathological features of intraocular medulloepithelioma with emphasis on the role of imaging to enable its differentiation from more common intraocular pathology.

Materials And Methods: We retrospectively analyzed the clinical, histopathological and imaging data of four children with intraocular medulloepithelioma.

Results: All four children had medulloepithelioma arising from the ciliary body. The children were imaged with US (n = 3), MRI (n = 4), whole-body (99m)Tc-MDP scintigraphy (n = 2) and CT (n = 1). All four children had enucleation of the involved eye. One tumor was a malignant teratoid variant, two tumors were malignant nonteratoid variants and one was a nonteratoid variant of uncertain malignant potential. None of the tumors had extraocular extension on histopathology or imaging. Two children had associated retinal detachment on US and MRI examinations. All tumors were iso/hyperintense to vitreous on T1-weighted and hypointense on T2-weighted MRI and showed marked contrast enhancement of the solid components. No calcifications were identified on US or CT examinations.

Conclusion: Our findings are consistent with previously reported cases of medulloepithelioma. This series emphasizes the roles of various imaging modalities, with pathological correlation, in differentiating the tumor from other ciliary body masses, in detecting tumor extension and in identifying associated ocular complications. In this series we also describe the results of postsurgical follow-up for tumor recurrence.
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http://dx.doi.org/10.1007/s00247-013-2718-xDOI Listing
October 2013

The effects of propofol on cerebral perfusion MRI in children.

Neuroradiology 2013 Aug 15;55(8):1049-1056. Epub 2013 May 15.

Department of Radiological Sciences, St. Jude Children's Research Hospital, MS 220, 262 Danny Thomas Place, Memphis, TN, 38105-3678, USA.

Introduction: The effects of anesthesia are infrequently considered when interpreting pediatric perfusion magnetic resonance imaging (MRI). The objectives of this study were to test for measurable differences in MR measures of cerebral blood flow (CBF) and cerebral blood volume (CBV) between non-sedated and propofol-sedated children, and to identify influential factors.

Methods: Supratentorial cortical CBF and CBV measured by dynamic susceptibility contrast perfusion MRI in 37 children (1.8-18 years) treated for infratentorial brain tumors receiving propofol (IV, n = 19) or no sedation (NS, n = 18) were compared between groups and correlated with age, hematocrit (Hct), end-tidal CO₂ (ETCO₂), dose, weight, and history of radiation therapy (RT). The model most predictive of CBF and CBV was identified by multiple linear regression.

Results: Anterior cerebral artery (ACA) and middle cerebral artery (MCA) territory CBF were significantly lower, and MCA territory CBV greater (p = 0.03), in IV than NS patients (p = 0.01, 0.04). The usual trend of decreasing CBF with age was reversed with propofol in ACA and MCA territories (r = 0.53, r = 0.47; p < 0.05). ACA and MCA CBF (r = 0.59, 0.49; p < 0.05) and CBV in ACA, MCA, and posterior cerebral artery territories (r = 0.73, 0.80, 0.52; p < 0.05) increased with weight in propofol-sedated children, with no significant additional influence from age, ETCO₂, hematocrit, or RT.

Conclusion: In propofol-sedated children, usual age-related decreases in CBF were reversed, and increases in CBF and CBV were weight-dependent, not previously described. Weight-dependent increases in propofol clearance may diminish suppression of CBF and CBV. Prospective study is required to establish anesthetic-specific models of CBF and CBV in children.
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http://dx.doi.org/10.1007/s00234-013-1187-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3720819PMC
August 2013

The impact of preparation and support procedures for children with sickle cell disease undergoing MRI.

Pediatr Radiol 2012 Oct 19;42(10):1223-8. Epub 2012 Jun 19.

Child Life Program, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 121, Memphis, TN 38105, USA.

Background: Children with sickle cell disease (SCD) often undergo MRI studies to assess brain injury or to quantify hepatic iron. MRI requires the child to lie motionless for 30-60 min, thus sedation/anesthesia might be used to facilitate successful completion of exams, but this poses additional risks for SCD patients. To improve children's ability to cope with MRI examinations and avoid sedation, our institution established preparation and support procedures (PSP).

Objective: To investigate the impact of PSP in reducing the need for sedation during MRI exams among children with SCD.

Materials And Methods: Data on successful completion of MRI testing were compared among 5- to 12-year-olds who underwent brain MRI or liver R2*MRI with or without receiving PSP.

Results: Seventy-one children with SCD (median age 9.85 years, range 5.57-12.99 years) underwent a brain MRI (n = 60) or liver R2*MRI (n = 11). Children who received PSP were more likely to complete an interpretable MRI exam than those who did not (30 of 33; 91% vs. 27 of 38; 71%, unadjusted OR = 4.1 (P = 0.04) and OR = 8.5 (P < 0.01) when adjusting for age.

Conclusion: PSP can help young children with SCD complete clinically interpretable, nonsedated MRI exams, avoiding the risks of sedation/anesthesia.
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http://dx.doi.org/10.1007/s00247-012-2422-2DOI Listing
October 2012

Topotecan and vincristine combination is effective against advanced bilateral intraocular retinoblastoma and has manageable toxicity.

Cancer 2012 Nov 19;118(22):5663-70. Epub 2012 Apr 19.

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

Background: New, effective chemotherapeutic agents are needed for intraocular retinoblastoma.

Methods: This institutional clinical trial sought to estimate the rate of response to 2 courses of vincristine and topotecan (VT) window therapy in patients with bilateral retinoblastoma and advanced disease (Reese-Ellsworth group IV or V) in at least 1 eye. The topotecan dose started at 3 mg/m(2) /day for 5 days and was adjusted to target a systemic exposure of 140 ± 20 ng/mL · hour. The vincristine dose was 0.05 mg/kg for patients <12 months of age and 1.5 mg/m(2) for those >12 months of age at diagnosis.

Results: From February 2005 to June 2010, 27 patients received VT window therapy. Median age at enrollment was 8.1 months (range, 0.7-22.1 months). Twenty-four patients (88.9%) responded to window therapy (95% confidence interval = 71.3%-96.9%). Hematologic toxicity comprised grade 4 neutropenia (n = 27), grade 3 anemia (n = 19), and grade 3/4 thrombocytopenia (n = 16). Thirteen patients had grade 3 nonhematologic toxicity. Granulocyte colony-stimulating factor support was added after 10 patients had been treated, and it significantly reduced the duration of grade 4 neutropenia (median, 7 vs 24 days; P < .001). Pharmacokinetic studies showed rapid changes in topotecan clearance rates during the first year of life.

Conclusions: The combination of topotecan and vincristine is effective for the treatment of advanced intraocular retinoblastoma. Granulocyte colony-stimulating factor treatment alleviates the duration of grade 4 neutropenia. Appropriate topotecan starting doses for patients 0-3, 3-6, 6-9, 9-12, and >12 months of age are specified.
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http://dx.doi.org/10.1002/cncr.27563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413782PMC
November 2012

US and MRI of pediatric ocular masses with histopathological correlation.

Pediatr Radiol 2012 Jun 31;42(6):738-49. Epub 2012 Mar 31.

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

We review our experience with unusual ocular pathologies, some mimicking retinoblastoma, that were referred to our institution during the past two decades. After presenting the imaging anatomy of the normal eye, we discuss pertinent clinical and pathological features, and illustrate the US and MRI appearance of retinoblastoma, medulloepithelioma, uveal melanoma, persistent fetal vasculature, Coats disease, corneal dermoid, retinal dysplasia and toxocara granuloma. Features useful in discriminating among these entities are emphasized.
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http://dx.doi.org/10.1007/s00247-012-2374-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530407PMC
June 2012

Hemodynamic responses to visual stimulation in children with sickle cell anemia.

Brain Imaging Behav 2011 Dec;5(4):295-306

Department of Radiological Sciences, St. Jude Children's Research Hospital, MS 220, 262 Danny Thomas Place, Memphis, TN 38105, USA.

Blood oxygenation level-dependent (BOLD) and cerebral blood flow (CBF)-based functional magnetic resonance imaging (fMRI) were used to measure primary visual cortex responses to photic stimulation in 23 children (12.4  ±  0.7 years old) with sickle cell anemia (SCA) and 21 clinical controls (11  ±  1.0 years old). The objectives were to investigate the effect of SCA on detection of brain activation with fMRI and to explore the relationship between fMRI responses and global cognitive function. The BOLD responses were diminished in children with SCA. Clinical indicators of disease severity were greatest in patients without detectable visual cortex activation, but blood hemoglobin concentration and resting CBF were not predictive of BOLD signal amplitude in the SCA patients. Unexpectedly, the BOLD signal amplitude was positively associated (r(s)  ≥  0.8, p  ≤  0.05) with Wechsler Abbreviated Scale of Intelligence scores, suggesting that fMRI may help clarify medical, hemodynamic, and neural factors that mediate adverse effects of SCA on neurocognitive function.
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http://dx.doi.org/10.1007/s11682-011-9133-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3620037PMC
December 2011

Sequencing of local therapy affects the pattern of treatment failure and survival in children with atypical teratoid rhabdoid tumors of the central nervous system.

Int J Radiat Oncol Biol Phys 2012 Apr 19;82(5):1756-63. Epub 2011 May 19.

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

Purpose: To assess the pattern of treatment failure associated with current therapeutic paradigms for childhood atypical teratoid rhabdoid tumors (AT/RT).

Methods And Materials: Pediatric patients with AT/RT of the central nervous system treated at our institution between 1987 and 2007 were retrospectively evaluated. Overall survival (OS), progression-free survival, and cumulative incidence of local failure were correlated with age, sex, tumor location, extent of disease, and extent of surgical resection. Radiotherapy (RT) sequencing, chemotherapy, dose, timing, and volume administered after resection were also evaluated.

Results: Thirty-one patients at a median age of 2.3 years at diagnosis (range, 0.45-16.87 years) were enrolled into protocols that included risk- and age-stratified RT. Craniospinal irradiation with focal tumor bed boost (median dose, 54 Gy) was administered to 18 patients. Gross total resection was achieved in 16. Ten patients presented with metastases at diagnosis. RT was delayed more than 3 months in 20 patients and between 1 and 3 months in 4; 7 patients received immediate postoperative irradiation preceding high-dose alkylator-based chemotherapy. At a median follow-up of 48 months, the cumulative incidence of local treatment failure was 37.5% ± 9%; progression-free survival was 33.2% ± 10%; and OS was 53.5% ± 10%. Children receiving delayed RT (≥1 month postoperatively) were more likely to experience local failure (hazard ratio [HR] 1.23, p = 0.007); the development of distant metastases before RT increased the risk of progression (HR 3.49, p = 0.006); and any evidence of disease progressionbefore RT decreased OS (HR 20.78, p = 0.004). Disease progression occurred in 52% (11/21) of children with initially localized tumors who underwent gross total resection, and the progression rate increased proportionally with increasing delay from surgery to RT.

Conclusions: Delayed RT is associated with a higher rate of local and metastatic disease progression in children with AT/RT. Current treatment regimens for pediatric patients with AT/RT are distinctly age stratified; novel protocols investigating RT volumes and sequencing are needed.
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http://dx.doi.org/10.1016/j.ijrobp.2011.02.059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530399PMC
April 2012

Spinal epidural lipomatosis in children with hematologic malignancies.

Ann Hematol 2011 Sep 22;90(9):1067-74. Epub 2011 Feb 22.

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

Abnormal fat deposition in the epidural space or spinal epidural lipomatosis (SEL) due to corticosteroid treatment or obesity may cause obstruction to cerebrospinal fluid flow. Little is known about SEL in patients with hematologic malignancies who require frequent lumbar punctures and corticosteroid treatment that places them at risk. Records and radiologic images of patients with SEL and leukemia or non-Hodgkin lymphoma (NHL) treated at a single institution from 1999-2009 were reviewed. Risk factors were compared with 405 control patients with leukemia. Fourteen patients with leukemia or NHL were diagnosed with SEL. The majority of patients underwent diagnostic imaging after unsuccessful lumbar punctures within 1 month of their primary diagnosis. Prior to SEL diagnosis, all patients received systemic and/or intrathecal corticosteroids. SEL diagnosis led to modification of intrathecal administration in eight patients, including Ommaya reservoir placement in four patients. All patients completed protocol-specified chemotherapy without neurologic symptoms or surgical intervention. Risk factors for developing SEL include older age and high body mass index. Investigation for SEL in leukemia or lymphoma patients with difficult lumbar punctures is warranted. Placement of an Ommaya reservoir may facilitate safe CNS-directed therapy in severely affected patients.
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http://dx.doi.org/10.1007/s00277-011-1183-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169011PMC
September 2011

Functional neuroimaging to characterize visual system development in children with retinoblastoma.

Invest Ophthalmol Vis Sci 2011 Apr 20;52(5):2619-26. Epub 2011 Apr 20.

Department of Radiological Sciences, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-2794, USA.

Purpose: To use functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) to investigate visual system development in children being treated for retinoblastoma.

Methods: Informed consent was obtained for all participants (N = 42) in this institutional review board-approved study. Participants were imaged with a 1.5-T scanner while under propofol sedation. Diagnostic brain and orbital imaging was followed by investigational functional neuroimaging, which included fMRI during photic stimulation through closed eyelids, to measure functional activation in the visual cortex, and DTI, to evaluate diffusion parameters of white matter tracts in the corpus callosum and the periventricular optic radiations. Analysis included 115 examinations of 39 patients with a median age of 16.4 months and age range from 1.5 to 101.5 months at first evaluation.

Results: The blood oxygen level-dependent signal was predominantly negative and located in the anterior visual cortex. Activation was affected by tumor lateralization (unilateral or bilateral), macular involvement, and retinal detachment. Patients who had undergone unilateral enucleation showed cortical dominance corresponding to the projection from the nasal hemiretina in the unaffected eye. Diffusion parameters followed a normal developmental trajectory in the optic radiations and corpus callosum, but variability was greater in the splenium than in the genu of the corpus callosum.

Conclusions: Longitudinal functional neuroimaging demonstrated important effects of disease and treatment. Therefore, fMRI and DTI may be useful for characterizing the impact of retinoblastoma on the developing visual system and improving the prediction of visual outcome in survivors.
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http://dx.doi.org/10.1167/iovs.10-5600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088553PMC
April 2011

p18Ink4c and p53 Act as tumor suppressors in cyclin D1-driven primitive neuroectodermal tumor.

Cancer Res 2009 Jan;69(2):440-8

Children's Cancer Center of Lebanon, American University of Beirut Medical Center, Beirut, Lebanon.

The retinoblastoma (RB) tumor suppressor pathway is likely important in primitive neuroectodermal tumors (PNET) of the brain. In fact, 10% to 15% of children born with RB mutations develop brain PNETs, commonly in the pineal gland. Cyclin D1, which in association with cyclin-dependent kinase (Cdk) 4 and Cdk6 phosphorylates and inactivates the RB protein, is expressed in 40% of sporadic medulloblastoma, a PNET of the cerebellum. To understand tumorigenic events cooperating with RB pathway disruption in brain PNET, we generated a transgenic mouse where cyclin D1 was expressed in pineal cells. Cyclin D1 enhanced pinealocyte proliferation, causing pineal gland enlargement. However, proliferation ceased beyond 2 weeks of age with reversal of Cdk4-mediated Rb phosphorylation despite continued expression of the transgene, and the pineal cells showed heterochromatin foci suggestive of a senescent-like state. In the absence of the p53 tumor suppressor, cell proliferation continued, resulting in pineal PNET that limited mouse survival to approximately 4 months. Interestingly, the Cdk inhibitor p18(Ink4c) was induced in the transgenic pineal glands independently of p53, and transgenic mice that lacked Ink4c developed invasive PNET, although at an older age than those lacking p53. Analogous to our mouse model, we found that children with heritable RB often had asymptomatic pineal gland enlargement that only rarely progressed to PNET. Our finding that the Cdk4 inhibitor p18(Ink4c) is a tumor suppressor in cyclin D1-driven PNET suggests that pharmacologic interventions to inhibit Cdk4 activity may be a useful chemoprevention or therapeutic strategy in cancer driven by primary RB pathway disruption.
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http://dx.doi.org/10.1158/0008-5472.CAN-08-1892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629408PMC
January 2009

Arterial spin-labeled perfusion combined with segmentation techniques to evaluate cerebral blood flow in white and gray matter of children with sickle cell anemia.

Pediatr Blood Cancer 2009 Jan;52(1):85-91

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

Background: Changes in cerebral perfusion are an important feature of the pathophysiology of sickle cell anemia (SCA); cerebrovascular ischemia occurs frequently and leads to neurocognitive deficits, silent infarcts, and overt stroke. Non-invasive MRI methods to measure cerebral blood flow (CBF) by arterial spin labeling (ASL) afford new opportunities to characterize disease- and therapy-induced changes in cerebral hemodynamics in patients with SCA. Recent studies have documented elevated gray matter (GM) CBF in untreated children with SCA, but no measurements of white matter (WM) CBF have been reported.

Procedures: Pulsed ASL with automated brain image segmentation-classification techniques were used to determine the CBF in GM, WM, and abnormal white matter (ABWM) of 21 children with SCA, 18 of whom were receiving hydroxyurea therapy.

Results: GM and WM CBF were highly associated (R(2) = 0.76, P < 0.0001) and the GM to WM CBF ratio was 1.6 (95% confidence interval: 1.43-1.83). Global GM CBF in our treated cohort was 87 +/- 24 mL/min/100 g, a value lower than previously reported in untreated patients with SCA. CBF was elevated in normal appearing WM (43 +/- 14 mL/min/100 g) but decreased in ABWM (6 +/- 12 mL/min/100 g), compared to published normal pediatric controls. Hemispheric asymmetry in CBF was noted in most patients.

Conclusions: These perfusion measurements suggest that hydroxyurea may normalize GM CBF in children with SCA, but altered perfusion in WM may persist. This novel combined approach for CBF quantification will facilitate prospective studies of cerebral vasculopathy in SCA, particularly regarding the effects of treatments such as hydroxyurea.
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http://dx.doi.org/10.1002/pbc.21745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480678PMC
January 2009

MRI abnormalities of the brain in one-year-old children with sickle cell anemia.

Pediatr Blood Cancer 2008 Nov;51(5):643-6

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

Background: Sickle cell anemia (SCA) frequently results in damage to the central nervous system (CNS), but the age of onset of these effects is uncertain. We performed MRI examinations of the brain in infants with SCA, who were evaluated as part of the multicenter randomized double-blinded Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG).

Methods: Determination of eligibility for enrollment in the trial originally required baseline MRI and magnetic resonance angiography (MRA) of the brain. A standardized imaging protocol was utilized across eight clinical centers. MRI/MRA exams were reviewed by a panel of three neurology/neuroradiology readers and interpretations reported to the coordinating center. Results were correlated with patient age, gender, history, WBC count, platelet count, hemoglobin (Hb), HbF level, score on the Bayley Scales of Infant Development, and velocity on transcranial Doppler ultrasonography (TCD).

Results: Twenty-three subjects with HbSS were examined at average age 13.7 months (range 10-18 months); 13 were male. Three (13%, CI: 3-34%) had silent infarcts on MRI, two in the right frontal area and one bilaterally. None had MRA abnormalities. The lesions were correlated with increased right-sided TCD velocity and low HbF level, but not with age, history, Hb level, developmental score, or left-sided velocity.

Conclusions: Silent brain infarcts occur in a small but significant number of infants with SCA as early as a year of age. This finding indicates a need for thorough evaluation of the CNS very early in life in children with SCA in order to develop timely intervention strategies.
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http://dx.doi.org/10.1002/pbc.21612DOI Listing
November 2008

Diffusion tensor imaging of brainstem tumors: axonal degeneration of motor and sensory tracts.

J Neurosurg Pediatr 2008 Apr;1(4):270-6

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

Object: Diffusion tensor (DT) imaging has been used to predict postoperative motor function in patients with supratentorial tumors. The authors sought to determine whether DT imaging and white matter tractography could detect axonal degeneration in patients with brainstem tumors.

Methods: A cross-sectional, retrospective study of 7 patients with brainstem tumors and 8 healthy volunteers was performed. The DT imaging data were normalized and regions of interest (ROIs) with the highest probability of sensory and motor connections were selected using the Talairach Atlas to identify the 3D millimetric coordinates of white matter tracts. An iterative process involving fractional anisotropy (FA), apparent diffusion coefficients (ADCs), and color maps was developed to precisely select ROIs in the bilateral sensory and motor tracts. The FA and ADC values were calculated for each ROI.

Results: The FA values of sensory and motor tracts significantly differed between the patient and healthy volunteer groups (p < 0.05), whereas no significant changes were found in the splenium or genu of the corpus callosum. The FA values were altered proximal and distal to the brainstem tumors with a bimodal peak of antegrade decreased FA involving second- and third-order sensory axons and retrograde decreased FA of motor axons.

Conclusions: This study demonstrates changes in diffusion properties of sensory and motor tracts consistent with degeneration to further characterize brainstem tumors in children, and the results warrant the planning of prospective trials. The rigorous methods the authors describe may provide valuable information when planning biopsies or debulking of unusual brainstem tumors, as well as improve prognostication of the possible functional tract recovery following therapy.
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http://dx.doi.org/10.3171/PED/2008/1/4/270DOI Listing
April 2008

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