The Impact of Persistent Leukoencephalopathy on Brain White Matter Microstructure in Long-Term Survivors of Acute Lymphoblastic Leukemia Treated with Chemotherapy Only.

BACKGROUND AND PURPOSE: Survivors of acute lymphoblastic leukemia are at risk for neurocognitive deficits and leukoencephalopathy. We performed a longitudinal assessment of leukoencephalopathy and its associations with long-term brain microstructural white matter integrity and neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia treated on a modern chemotherapy-only protocol. MATERIALS AND METHODS: One hundred seventy-three survivors of acute lymphoblastic leukemia (49% female), treated on a chemotherapy-only protocol, underwent brain MR imaging during active therapy and repeat imaging and neurocognitive testing at follow-up (median, 13.5 years of age; interquartile range, 10.7-17.6 years; median time since diagnosis, 7.5 years; interquartile range, 6.3-9.1 years). Persistence of leukoencephalopathy was examined in relation to demographic and treatment data and to brain DTI in major fiber tracts and neurocognitive testing at follow-up. RESULTS: Leukoencephalopathy was found in 52 of 173 long-term survivors (30.0%) and persisted in 41 of 52 (78.8%) who developed it during therapy. DTI parameters were associated with leukoencephalopathy in multiple brain regions, including the corona radiata (fractional anisotropy, P = .001; mean diffusivity, P < .001), superior longitudinal fasciculi (fractional anisotropy, P = .02; mean diffusivity, P < .001), and superior fronto-occipital fasciculi (fractional anisotropy, P = .006; mean diffusivity, P < .001). Mean diffusivity was associated with neurocognitive impairment including in the genu of the corpus callosum (P = .04), corona radiata (P = .02), and superior fronto-occipital fasciculi (P = .02). CONCLUSIONS: Leukoencephalopathy during active therapy and neurocognitive impairment at long-term follow-up are associated with microstructural white matter integrity. DTI may be more sensitive than standard MR imaging for detection of clinically consequential white matter abnormalities in childhood acute lymphoblastic leukemia survivors treated with chemotherapy and in children undergoing treatment.

Measurable Supratentorial White Matter Volume Changes in Patients with Diffuse Intrinsic Pontine Glioma Treated with an Anti-Vascular Endothelial Growth Factor Agent, Steroids, and Radiation.

BACKGROUND AND PURPOSE: Assessing the response to treatment in infiltrative brain tumors by using lesion volume-based response criteria is challenging. We hypothesized that in such tumors, volume measurements alone may not accurately capture changes in actual tumor burden during treatment. We longitudinally evaluated volume changes in both normal-appearing supratentorial white matter and the brain stem lesions in patients treated for diffuse intrinsic pontine glioma to determine to what extent adjuvant systemic therapies may skew the accuracy of tumor response assessments based on volumetric analysis. MATERIALS AND METHODS: The anatomic MR imaging and diffusion tensor imaging data of 26 patients with diffuse intrinsic pontine glioma were retrospectively analyzed. Treatment included conformal radiation therapy in conjunction with vandetanib and dexamethasone. Volumetric and diffusion data were analyzed with time, and differences between time points were evaluated statistically. RESULTS: Normalized brain stem lesion volume decreased during combined treatment (slope = -0.222, P < .001) and increased shortly after completion of radiation therapy (slope = 0.422, P < .001). Supratentorial white matter volume steadily and significantly decreased with time (slope = -0.057, P < .001). CONCLUSIONS: Longitudinal changes in brain stem lesion volume are robust; less pronounced but measurable changes occur in the supratentorial white matter. Volume changes in nonirradiated supratentorial white matter during the disease course reflect the effects of systemic medication on the water homeostasis of normal parenchyma. Our data suggest that adjuvant nontumor-targeted therapies may have a more substantial effect on lesion volume changes than previously thought; hence, an apparent volume decrease in infiltrative tumors receiving combined therapies may lead to overestimation of the actual response and tumor control.

MRI Evaluation of Non-Necrotic T2-Hyperintense Foci in Pediatric Diffuse Intrinsic Pontine Glioma.

BACKGROUND AND PURPOSE: The conventional MR imaging appearance of diffuse intrinsic pontine glioma suggests intralesional histopathologic heterogeneity, and various distinct lesion components, including T2-hypointense foci, have been described. Here we report the prevalence, conventional MR imaging semiology, and advanced MR imaging features of non-necrotic T2-hyperintense foci in diffuse intrinsic pontine glioma. MATERIALS AND METHODS: Twenty-five patients with diffuse intrinsic pontine gliomas were included in this study. MR imaging was performed at 3T by using conventional and advanced MR imaging sequences. Perfusion (CBV), vascular permeability (ve, Ktrans), and diffusion (ADC) metrics were calculated and used to characterize non-necrotic T2-hyperintense foci in comparison with other lesion components, namely necrotic T2-hyperintense foci, T2-hypointense foci, peritumoral edema, and normal brain stem. Statistical analysis was performed by using Kruskal-Wallis and Wilcoxon rank sum tests. RESULTS: Sixteen non-necrotic T2-hyperintense foci were found in 12 tumors. In these foci, ADC values were significantly higher than those in either T2-hypointense foci (P = .002) or normal parenchyma (P = .0002), and relative CBV values were significantly lower than those in either T2-hypointense (P = .0002) or necrotic T2-hyperintense (P = .006) foci. Volume transfer coefficient values in T2-hyperintense foci were lower than those in T2-hypointense (P = .0005) or necrotic T2-hyperintense (P = .0348) foci. CONCLUSIONS: Non-necrotic T2-hyperintense foci are common, distinct lesion components within diffuse intrinsic pontine gliomas. Advanced MR imaging data suggest low cellularity and an early stage of angioneogenesis with leaky vessels resulting in expansion of the extracellular space. Because of the lack of biopsy validation, the underlying histoarchitectural and pathophysiologic changes remain unclear; therefore, these foci may correspond to a poorly understood biologic event in tumor evolution.

Assessing vascular effects of adding bevacizumab to neoadjuvant chemotherapy in osteosarcoma using DCE-MRI.

BACKGROUND: The purpose of this study was to assess the impact of bevacizumab alone and in combination with cytotoxic therapy on tumour vasculature in osteosarcoma (OS) using DCE-MRI. METHODS: Six DCE-MRI and three (18)F-FDG PET examinations were scheduled in 42 subjects with newly diagnosed OS to monitor the response to antiangiogenic therapy alone and in combination with cytotoxic therapy before definitive surgery (week 10). Serial DCE-MRI parameters (K(trans), v(p), and v(e)) were examined for correlation with FDG-PET (SUV(max)) and association with drug exposure, and evaluated with clinical outcome. RESULTS: K(trans) (P=0.041) and v(p) (P=0.001) significantly dropped from baseline at 24 h after the first dose of bevacizumab alone, but returned to baseline by 72 h. Greater exposure to bevacizumab was correlated with larger decreases in v(p) at day 5 (P=0.04) and week 10 (P=0.02). A lower K(trans) at week 10 was associated with greater percent necrosis (P=0.024) and longer event-free survival (P=0.034). CONCLUSIONS: This is the first study to demonstrate significant changes of the plasma volume fraction and vascular leakage in OS with bevacizumab alone. The combination of demonstrated associations between drug exposure and imaging metrics, and imaging metrics and patient survival during neoadjuvant therapy, provides a compelling rationale for larger studies using DCE-MRI to assess vascular effects of therapy in OS.

Elevated cerebral blood volume contributes to increased FLAIR signal in the cerebral sulci of propofol-sedated children.

BACKGROUND AND PURPOSE: Hyperintense FLAIR signal in the cerebral sulci of anesthetized children is attributed to supplemental oxygen (fraction of inspired oxygen) but resembles FLAIR hypersignal associated with perfusion abnormalities in Moyamoya disease and carotid stenosis. We investigated whether cerebral perfusion, known to be altered by anesthesia, contributes to diffuse signal intensity in sulci in children and explored the relative contributions of supplemental oxygen, cerebral perfusion, and anesthesia to signal intensity in sulci. MATERIALS AND METHODS: Supraventricular signal intensity in sulci on pre- and postcontrast T2 FLAIR images of 24 propofol-sedated children (6.20 ± 3.28 years) breathing supplemental oxygen and 18 nonsedated children (14.28 ± 2.08 years) breathing room air was graded from 0 to 3. The Spearman correlation of signal intensity in sulci with the fraction of inspired oxygen and age in 42 subjects, and with dynamic susceptibility contrast measures of cortical CBF, CBV, and MTT available in 25 subjects, were evaluated overall and compared between subgroups. Factors most influential on signal intensity in sulci were identified by stepwise logistic regression. RESULTS: CBV was more influential on noncontrast FLAIR signal intensity in sulci than the fraction of inspired oxygen or age in propofol-sedated children (CBV: r = 0.612, P = .026; fraction of inspired oxygen: r = -0.418, P = .042; age: r = 0.523, P = .009) and overall (CBV: r = 0.671, P = .0002; fraction of inspired oxygen: r = 0.442, P = .003; age: r = -0.374, P = .015). MTT (CBV/CBF) was influential in the overall cohort (r = 0.461, P = .020). Signal intensity in sulci increased with contrast in 45% of subjects, decreased in none, and was greater (P < .0001) in younger propofol-sedated subjects, in whom the signal intensity in sulci increased with age postcontrast (r = .600, P = .002). CONCLUSIONS: Elevated cortical CBV appears to contribute to increased signal intensity in sulci on noncontrast FLAIR in propofol-sedated children. The effects of propofol on age-related cerebral perfusion and vascular permeability may play a role.

Cognitive outcomes following contemporary treatment without cranial irradiation for childhood acute lymphoblastic leukemia.

BACKGROUND: Treatment of acute lymphoblastic leukemia (ALL) has included the use of prophylactic cranial irradiation in up to 20% of children with high-risk disease despite known cognitive risks of this treatment modality. METHODS: Patients enrolled on the St Jude ALL Total Therapy Study XV, which omitted prophylactic cranial irradiation in all patients, were assessed 120 weeks after completion of consolidation therapy (n = 243) using a comprehensive cognitive battery. χ(2) analysis was used to compare the percentage of below-average performers among the entire ALL patient group to the expected rate based on the normative sample. Univariate logistic regression was used to estimate the effect of intensity of chemotherapy (treatment arm), age at diagnosis, and sex on the probability of below-average performance. All statistical tests were two-sided. RESULTS: Overall, the ALL group had a statistically significantly higher risk for below-average performance on a measure of sustained attention (67.31% more than 1 SD below the normative mean for omission errors, P < .001) but not on measures of intellectual functioning, academic skills, or memory. Patients given higher intensity chemotherapy were at greater risk for below-average performance compared with those given lower intensity therapy on measures of processing speed (27.14% vs 6.25%, P = .009) and academic abilities (Math Reasoning: 18.60% vs 3.90%, P = .008; Word Reading: 20.00% vs 2.60%, P = .007; Spelling: 27.91% vs 3.90%, P = .001) and had higher parent-reported hyperactivity (23.00% vs 9.84%, P = .018) and learning problems (35.00% vs 16.39%, P = .005). Neither age at diagnosis nor sex was associated with risk for below-average cognitive performance. CONCLUSIONS: Omitting cranial irradiation may help preserve global cognitive abilities, but treatment with chemotherapy alone is not without risks. Caregiver education and development of interventions should address both early attention deficits and cognitive late effects.

Quantitative diffusion-weighted and dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging analysis of T2 hypointense lesion components in pediatric diffuse intrinsic pontine glioma.

BACKGROUND AND PURPOSE: Focal anaplasia characterized by T2 hypointensity, signal-intensity enhancement on postcontrast T1-weighted MR imaging and restricted water diffusion has been reported in a patient with juvenile pilocytic astrocytoma. We identified T2(HOF) with these MR imaging characteristics in children with DIPG and hypothesized that these represent areas of focal anaplasia; and may, therefore, have increased perfusion properties and should be characterized by increased perfusion. Thus, we used DSC to investigate our hypothesis. MATERIALS AND METHODS: We retrospectively reviewed the baseline MR imaging scans of 86 patients (49 girls, 37 boys; median age, 6.1 years; range, 1.1-17.6 years) treated for DIPG at our hospital (2004-2009). T2(HOF) with the described MR imaging characteristics was identified in 10 patients. We used a region of interest-based approach to compare the ADC, FA, rCBV, rCBF, and rMTT of T2(HOF) with those of the typical T2(HRT). RESULTS: The ADC of T2(HOF) with the specified MR imaging characteristics was significantly lower than that of T2(HRT) (range, 0.71-1.95 µm(2)/ms versus 1.36-2.13 µm(2)/ms; P < .01); and the FA (range, 0.12-0.34 versus 0.07-0.24; P = .03) and rCBV (range, 0.4-2.62 versus 0.23-1.57; P = .01) values of T2(HOF)s were significantly higher. CONCLUSIONS: Our data suggest that T2(HOF) in DIPG may represent areas of focal anaplasia and underline the importance of regional, rather than global, tumor-field analysis. T2(HOF) may be the ideal target when stereotactic biopsy of tumors that present with an inhomogeneous T2 signal intensity is considered.

Cerebellocerebral diaschisis is the likely mechanism of postsurgical posterior fossa syndrome in pediatric patients with midline cerebellar tumors.

BACKGROUND AND PURPOSE: PFS occurs in approximately 25% of pediatric patients receiving surgery for midline posterior fossa tumors. Increasing evidence suggests that PFS represents a complex supratentorial cortical dysfunction related to surgery-induced disruption of critical cerebellocerebral connections. The purpose of this study was to determine whether a consistent surgical damage pattern may be identified in patients with PFS by early postoperative anatomic imaging analysis of the pECP and to test whether DSC can detect corresponding changes in cerebral cortical perfusion to indicate a secondary, remote functional disturbance, which could suggest a diaschisis-like pathomechanism. MATERIALS AND METHODS: Eleven patients with postoperative PFS were evaluated retrospectively and were paired with age- and sex-matched control subjects in whom PFS did not develop. MR imaging work-up included DSC within 3 to 4 weeks after surgery as well as early postoperative anatomic imaging to evaluate components of the pECP. RESULTS: DSC showed significant decreases in CBF within frontal regions (P < .05) and a trend to global cerebral cortical hypoperfusion in patients with PFS. Logistic regression analysis suggested a strong (potentially predictive) relationship between bilateral damage to pECP and the development of PFS (P = .04). CONCLUSIONS: Our data suggest that the primary cause of PFS is the bilateral surgical damage to the pECP. This leads to a trans-synaptic cerebral cortical dysfunction (a form of bilateral crossed cerebellocerebral diaschisis), which manifests with DSC-detectable global, but dominantly frontal, cortical hypoperfusion in patients with patients with PFS compared with age- and sex-matched control subjects.

Voxel-based analysis of T2 hyperintensities in white matter during treatment of childhood leukemia.

BACKGROUND AND PURPOSE: White matter (WM) hyperintensities on T2-weighted MR imaging are the most common imaging manifestation of neurotoxic effects of therapy for central nervous system (CNS) prophylaxis in childhood acute lymphoblastic leukemia (ALL). This study uses voxel-based analyses (VBA) of T2-weighted imaging of patients during treatment to identify which WM regions are preferentially damaged. MATERIALS AND METHODS: Two sets of conventional T2-weighted axial images were acquired on a 1.5T MR imaging scanner from 197 consecutive patients (85 female, 112 male; aged 1.0-18.9 years) enrolled on an institutional ALL treatment protocol. Images were acquired after completion of induction therapy and after the final of the 4 courses of intravenous high-dose methotrexate in consolidation therapy (3.9 +/- 0.8 months apart). Voxel-wise statistical testing of the incremental change between normalized longitudinal T2 images was performed with radiologist reading (normal or abnormal) and treatment risk-group as covariates. RESULTS: Two highly significant bilateral clusters of T2 signal intensity change were identified in both 1-group and 2-group analyses. The regions were symmetric in size, shape, and average signal intensity. Increased T2-weighted signal intensity from these regions both within and between examinations were nonlinear functions of age at examination, and the difference between the examinations was greater for older subjects who received more intense therapy. CONCLUSIONS: These analyses identified specific WM tracts involving predominantly the anterior, superior, and posterior corona radiata and superior longitudinal fasciculus, which were at increased risk for the development of T2-weighted hyperintensities during therapy for childhood ALL. These vulnerable regions may be the cause of subsequent cognitive difficulties consistently observed in survivors.

Tumor volume or dynamic contrast-enhanced MRI for prediction of clinical outcome of Ewing sarcoma family of tumors.

BACKGROUND: The identification of risk factors that predict poor clinical outcome at the time of diagnosis could lead to intensified early therapy and improved outcome for pediatric patients with Ewing sarcoma family of tumors (ESFT). OBJECTIVE: To compare the effectiveness of static magnetic resonance (MR) imaging measurements of tumor volume with variables obtained by dynamic contrast-enhanced MR imaging (DEMRI) in predicting ESFT outcome. METHODS: MR examinations that included DEMRI were retrospectively reviewed. The analyses included 45 examinations of 21 patients with ESFT (performed from 1992 to 1996). Tumor volumes were measured on the static MR images, and the regions of interest were selected for DEMRI analysis. The relationships of static MR imaging and DEMRI variables with the probability of progression-free survival (PFS) and disease-free survival (DFS) were determined. RESULTS: Larger tumor volume at the time of diagnosis predicted poorer PFS and DFS estimates. No DEMRI variable predicted outcome. CONCLUSION: Determination of tumor volume by static MR imaging at the time of diagnosis is a simple and reliable method of predicting the clinical outcome of patients with ESFT. DEMRI is not as reliable a technique as static MR imaging for predicting the outcome of these patients.

Dynamic magnetic resonance imaging of regional contrast access as an additional prognostic factor in pediatric osteosarcoma.

BACKGROUND: The purpose of this article was to evaluate the utility of a pharmacokinetically modeled measure of regional contrast access, based on dynamic contrast-enhanced magnetic resonance imaging (MRI) studies after preoperative chemotherapy, as a predictor of disease free survival in osteosarcoma. METHODS: The kinetic parameters of a two-compartment pharmacokinetic model of MRI contrast agent accumulation were analyzed in relation to disease free survival in 31 patients who received protocol-based therapy for nonmetastatic osteosarcoma of the extremities. The modeled exchange rate of contrast between the plasma and the tumor extravascular extracellular fluid space served as a measure of regional contrast access. The prognostic impact of both the clinically accepted standard of histologic evaluation of tumor necrosis and the regional contrast access were analyzed with tumor size as an influential factor. RESULTS: Although the histologic grade of response was not a statistically significant prognostic factor in these patients (P = 0.884), regional contrast access after preoperative chemotherapy was significantly predictive of disease free survival (P = 0.035) in the Cox proportional hazards model. Lower regional access before surgery and smaller tumor size were associated with a better treatment outcome. Log-rank analyses of Kaplan-Meier curves indicated that the impact of regional access was most pronounced in patients with larger tumors (P = 0.052). Higher regional access at presentation also was associated significantly with greater decreases during therapy. CONCLUSIONS: Dynamic MRI estimates of regional contrast access after preoperative chemotherapy, when combined with tumor size, holds promise for the early identification of patients at risk of recurrence. The availability of such response predictors could facilitate the development of risk-adapted treatment approaches.

Prospective evaluation of the brain in asymptomatic children with neurofibromatosis type 1: relationship of macrocephaly to T1 relaxation changes and structural brain abnormalities.

BACKGROUND AND PURPOSE: Mutation of the neurofibromatosis type 1 (NF-1) gene may be associated with abnormal growth control in the brain. Because macrocephaly could be a sign of abnormal brain development and because 30% to 50% of children with NF-1 display macrocephaly in the absence of hydrocephalus, we sought to determine the relationship between macrocephaly and other brain abnormalities in young subjects with NF-1. These subjects were free of brain tumor, epilepsy, or other obvious neurologic problems. METHODS: We prospectively screened 18 neurologically asymptomatic subjects with NF-1, ages 6 to 16 years, using clinical measures, psychometric testing, conventional MR imaging, and quantitative MR imaging to measure T1. RESULTS: Cranial circumference was 2 or more SDs above the age norm in seven (39%) of 18 subjects, a frequency of macrocephaly 17-fold higher than normal. Conventional MR imaging showed abnormalities in all 18 children, although there were more extensive abnormalities in subjects with macrocephaly. Macrocephaly in NF-1 was associated with enlargement of multiple brain structures, and brain T1 in macrocephalic subjects was reduced with respect to controls in the genu, frontal white matter, caudate, putamen, thalamus, and cortex. In normocephalic subjects, T1 was reduced only in the genu and splenium. Volumetric analysis showed that macrocephaly was associated specifically with enlargement of white matter volume. CONCLUSION: Neurologically asymptomatic children with NF-1 showed macrocephaly, cognitive deficit, enlarged brain structures, and abnormally low brain T1. Macrocephaly in children with NF-1 may be associated with characteristic alterations in brain development, marked by more widespread and significant changes in T1, greater enlargement of midline structures, and greater volume of white matter.

Patterns of intellectual development among survivors of pediatric medulloblastoma: a longitudinal analysis.

PURPOSE: To examine two competing hypotheses relating to intellectual loss among children treated for medulloblastoma (MB): Children with MB either: (1) lose previously learned skills and information; or (2) acquire new skills and information but at a rate slower than expected compared with healthy same-age peers. PATIENTS AND METHODS: Forty-four pediatric MB patients were evaluated who were treated with postoperative radiation therapy (XRT) with or without chemotherapy. After completion of XRT, a total of 150 examinations were conducted by use of the child version of the Wechsler Intelligence SCALES: These evaluations provided a measure of intellectual functioning called the estimated full-scale intelligence quotient (FSIQ). Changes in patient performance corrected for age (scaled scores) as well as the uncorrected performance (raw scores) were analyzed. RESULTS: At the time of the most recent examination, the obtained mean estimated FSIQ of 83.57 was more than one SD below expected population norms. A significant decline in cognitive performance during the time since XRT was demonstrated, with a mean loss of 2.55 estimated FSIQ points per year (P =.0001). An analysis for the basis of the intelligence quotient (IQ) loss revealed that subtest raw score values increased significantly over time since XRT, but the rate of increase was less than normally expected, which resulted in decreased IQ scores. CONCLUSION: These results support the hypothesis that MB patients demonstrate a decline in IQ values because of an inability to acquire new skills and information at a rate comparable to their healthy same-age peers, as opposed to a loss of previously acquired information and skills.

Immediate neurocognitive effects of methylphenidate on learning-impaired survivors of childhood cancer.

PURPOSE: To test if methylphenidate (MPH) has an objective beneficial effect on immediate performance on tests of neurocognitive functions among learning-impaired survivors of childhood acute lymphoblastic leukemia (ALL) and malignant brain tumors (BT). PATIENTS AND METHODS: From July 1, 1997 through December 31, 1998, 104 long-term survivors of childhood ALL or a malignant BT completed neurocognitive screening for learning impairments and concurrent problems with sustained attention. Eligibility criteria for the MPH trial included an estimated intelligence quotient greater than 50, academic achievement in the 16(th) percentile or lower for age in reading, math, or spelling, and an ability to sustain attention on a computerized version of the Conners' Continuous Performance Test (CPT) in the 16(th) percentile or lower for age and sex. Of the 104, 32 (BT, n = 25; ALL, n = 7) were eligible on the basis of these a priori criteria for a randomized, double-blinded, placebo-controlled trial of MPH. The patients ingested a placebo (lactose) or MPH (0.6 mg/kg; 20 mg maximum) and repeated selected portions of the screening battery 90 minutes later. RESULTS: Compared to the 17 patients randomized to the placebo group, the 15 patients randomized to the MPH group had a significantly greater improvement on the CPT for sustained attention (errors of omission, P =.015) and overall index (P =.008) but not for errors of commission (indicative of impulsiveness) nor reaction times. A trend for greater improvement in the MPH group on a measure of verbal memory failed to reach statistical significance. No trend was observed for MPH effectiveness in improving learning of a word association task. No significant side effects from MPH were observed. CONCLUSION: MPH resulted in a statistically significant improvement on measures of attention abilities that cannot be explained by placebo or practice effects.

Risks of young age for selected neurocognitive deficits in medulloblastoma are associated with white matter loss.

PURPOSE: To test the hypothesis that inadequate development of normal-appearing white matter (NAWM) is associated with the relationship between young age at the time of craniospinal irradiation (CRT) and deficient neurocognitive performance in survivors of childhood medulloblastoma. PATIENTS AND METHODS: Forty-two patients treated since 1985 participated in this cross-sectional study. All had been treated with CRT with or without chemotherapy and had survived 1 or more years after treatment. Neurocognitive evaluations were conducted with tests of intellect (intelligent quotient; IQ), verbal memory, and sustained attention. Quantitative magnetic resonance imaging, using a hybrid neural network, assessed the volume of NAWM. RESULTS: Neurocognitive test results were below normal expectations for age at the time of testing. A young age at CRT was significantly associated with worse performance on all neurocognitive tests except that of verbal memory. An increased time from completion of CRT was significantly associated with worse performance on all neurocognitive tests except that of sustained attention. After statistically controlling for the effects of time from CRT, we examined the association of NAWM with neurocognitive test results. These analyses revealed that NAWM accounted for a significant amount of the association between age at CRT and IQ, factual knowledge, and verbal and nonverbal thinking, but not sustained attention or verbal memory. CONCLUSION: The present results suggest that, at least for some cognitive functions, deficient development and/or loss of NAWM after CRT may provide a neuroanatomical substrate for the adverse impact of a young age at the time of CRT.

Subtle white matter volume differences in children treated for medulloblastoma with conventional or reduced dose craniospinal irradiation.

Medulloblastoma is the most common malignant brain tumor in children, and approximately seventy percent of average-risk patients will achieve long-term survival. Craniospinal irradiation (CSI), combined with chemotherapy and surgery, is currently the mainstay of treatment but places children who survive at risk for serious neurocognitive sequelae. These sequelae are intensified with a younger age at treatment, greater elapsed time following treatment, and an increased radiation dose. Many newer treatment approaches have attempted to address this problem by reducing the dose of the CSI component of radiation therapy while maintaining the current survival rates. This study evaluates longitudinal MR imaging during therapy to assess the impact of the two CSI doses (conventional [36 Gy] and reduced [23.4 Gy]) on normal appearing white matter volumes (NAWMV) evaluated in a single index slice. Twenty-six children and young adults at least three years of age enrolled on an institutional protocol for newly diagnosed, previously untreated primary medulloblastoma had at least four MR examinations over a minimum nine month period following CSI. These serial volumes were evaluated as a function of time since CSI in three analyses: 1) all subjects, 2) subjects stratified by age at CSI, and 3) subjects stratified by CSI dose. The first analysis demonstrated that medulloblastoma patients treated with CSI have a significant loss of NAWMV in contradistiction to normally expected maturation. Stratifying the patients by age at CSI found no significant differences in the rate of NAWMV loss. The final analysis stratified the patients by CSI dose and revealed that the rate of NAWMV loss was 23% slower in children receiving reduced-dose. Serial quantitative MR measures of NAWMV may provide a neuroanatomical substrate for assessing functional impact of CSI on normal brain function following treatment for medulloblastoma.

Fast adipose tissue (FAT) assessment by MRI.

We report a method of fast adipose tissue (FAT) assessment to characterize the quantity, and distribution of abdominal adipose tissue. Whole-volume coverage of the abdomen was obtained using 31 contiguous transverse T(1)-weighted images from 16 obese females. A radiologist manually traced all adipose tissue volumes in the images, while a physiologist used an automated method to measure adipose tissue in a single image at the level of the umbilicus. Automated analysis of the umbilicus-level image was significantly correlated with values obtained by manual analysis of the entire abdomen (p < 0. 001). There was good agreement between the automated umbilicus-level image method and the manual whole abdomen method for subcutaneous adipose tissue (r(2) = 0.958), visceral adipose tissue (r(2) = 0. 753), and total adipose tissue (r(2) = 0.941). The automated method required 6 min vs 2 h for the manual method.

Accuracy of MR imaging for detecting epiphyseal extension of osteosarcoma.

BACKGROUND: Too few patients are receiving epiphyseal-sparing limb salvage procedures for osteosarcoma. OBJECTIVE: To determine how magnetic resonance (MR) imaging can best predict the epiphyseal extension of osteosarcoma. MATERIALS AND METHODS: Forty children underwent complete pretreatment static and dynamic contrast-enhanced MR imaging (DEMRI). Static MR images [T1-weighted and short tau inversion recovery (STIR)] of the epiphyses were read in three ways: (1) for suspicion of any abnormality (tumor or edema), (2) for suspicion of tumor, excluding suspected edema, and (3) validating the second method by using a scale to rate the likelihood of tumor. Presentation imaging was compared to histopathologic findings after chemotherapy and resection. The receiver operating characteristic (ROC) method was used to analyze the scaled ratings of static MR and DEMRI values. RESULTS: At delayed resection, 20 of 40 children with osteosarcoma had confirmed epiphyseal tumor; however, 32 epiphyses were abnormal on STIR and 28 abnormal on T1. Differentiating suspected tumor from edema increased the accuracy to an Az (area under the ROC curve) of 0.94 for both T1-weighted and STIR static sequences. T1-weighted MR had better specificity and STIR better sensitivity at any given rating. DEMRI was slightly less accurate (Az = 0.90). CONCLUSION: Static MR imaging most accurately detected epiphyseal extension of osteosarcoma when readers distinguished suspected tumor from edematous or normal tissue.

More than meets the eye: significant regional heterogeneity in human cortical T1.

Segmented k-space acquisition of data was used to decrease the acquisition time and to increase the imaging resolution of the precise and accurate inversion recovery (PAIR) method of measuring T(1). We validated the new TurboPAIR method by measuring T(1) in 158 regions of interest in 12 volunteers, using both PAIR and TurboPAIR. We found a 3% difference between methods, which could be corrected by linear regression. After validation, the TurboPAIR method was used to test a hypothesis that there is significant regional heterogeneity in cortical T(1). We measured cortical gray matter T(1) in 11 right-handed volunteers, in 48 regions of interest scattered over frontal and parietal cortex, and in 46 ROIs along the central sulcus (CS). We found that T(1) in the CS is less than T(1) elsewhere in the cortex (p<0.001), and that there is considerable hemispheric asymmetry in T(1) in gray matter, but not in white matter. In central gray structures (caudate, thalamus, nucleus pulvinarus), and in the posterior CS (sensory cortex), right hemisphere T(1) was significantly greater than left hemisphere T(1) (p< or =0.004). In cortical gray matter of the frontal lobe and anterior CS (motor cortex), left hemisphere T(1) was significantly greater than right hemisphere T(1) (p< or =0.003). These findings demonstrate that there is considerable regional heterogeneity in human cortical T(1) that is unexplained by differences in tissue iron content, but may be evidence of an inherent anatomic asymmetry of the brain.

Evolution from empirical dynamic contrast-enhanced magnetic resonance imaging to pharmacokinetic MRI.

For chemotherapy to be effective against cancers which grow as solid tumors, agents must reach all tumor cells in effective quantities. Although many clinical trials include studies of the pharmacokinetics of the agents in body fluids such as blood or cerebrospinal fluid (CSF), there is presently no widely applicable way to determine access of chemotherapeutic agents to all regions of a solid tumor in an individual patient. This review discusses a relatively new methodology in MR imaging - dynamic contrast-enhanced imaging for exploring tumor microcirculation and drug access by imaging the uptake, or leakage, of contrast agent into tumor interstitial (extracellular and extravascular) space. The aims and methods of dynamic contrast-enhanced MRI evaluations to measure contrast uptake are distinguished from dynamic contrast-enhanced MRI to measure blood volume or flow, by MR imaging of the first-pass effects of a contrast bolus. Measures of contrast uptake by dynamic MRI have demonstrated a convincing ability to aid in diagnosing the presence of viable tumor and to measure response for a range of human tumors. This body of clinical results will be summarized. While questions remain to be answered about how to extract non-invasive pharmacokinetic measures of drug access from these novel dynamic imaging methods, we are optimistic that these methods can provide important new clinical measures that reflect the range of biological variation within and between naturally-occurring solid tumors.