Sridhar Vajapeyam

Lack of Efficacy of Bevacizumab Plus Irinotecan in Children With Recurrent Malignant Glioma and Diffuse Brainstem Glioma: A Pediatric Brain Tumor Consortium Study

PURPOSE A phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in children with recurrent malignant glioma (MG) and intrinsic brainstem glioma (BSG). PATIENTS AND METHODS Eligible patients received two doses of BVZ intravenously (10 mg/kg) 2 weeks apart and then BVZ plus CPT-11 every 2 weeks until progressive disease, unacceptable toxicity, or a maximum of 2 years of therapy. Correlative studies included diffusion weighted and T1 dynamic contrast-enhanced permeability imaging, BVZ pharmacokinetics, and estimation of vascular endothelial growth factor receptor 2 (VEGFR-2) phosphorylation in peripheral blood mononuclear cells (PBMC) after single-agent BVZ. RESULTS Thirty-one evaluable patients received a median of two courses of BVZ plus CPT-11 (range, 1 to 19). No sustained responses were observed in either stratum. Median time to progression for all 34 eligible patients enrolled was 127 days for MG and 71 days for BSG. Progression-free survival rates at 6 months were 41.8% and 9.7% for MG and BSG, respectively. Toxicities related to BVZ included grade 1 to 3 fatigue in seven patients, grade 1 to 2 hypertension in seven patients, grade 1 CNS hemorrhage in four patients, and grade 4 CNS ischemia in two patients. The mean diffusion ratio decreased after two doses of BVZ in patients with MG only. Vascular permeability parameters did not change significantly after therapy in either stratum. Inhibition of VEGFR-2 phosphorylation in PBMC was detected in eight of 11 patients after BVZ exposure. CONCLUSION BVZ plus CPT-11 was well-tolerated but had minimal efficacy in children with recurrent malignant glioma and brainstem glioma.

Biexponential Diffusion Tensor Analysis of Human Brain Diffusion Data

Several studies have shown that in tissues over an extended range of b‐factors, the signal decay deviates significantly from the basic monoexponential model. The true nature of this departure has to date not been identified. For the current study, line scan diffusion images of brain suitable for biexponential diffusion tensor analysis were acquired in normal subjects on a clinical MR system. For each of six noncollinear directions, 32 images with b‐factors ranging from 5 to 5000 s/mm2 were collected. Biexponential fits yielded parameter maps for a fast and a slow diffusion component. A subset of the diffusion data, consisting of the images obtained at the conventional range of b‐factors between 5 and 972 s/mm2, was used for monoexponential diffusion tensor analysis. Fractional anisotropy (FA) of the fast‐diffusion component and the monoexponential fit exhibited no significant difference. FA of the slow‐diffusion biexponential component was significantly higher, particularly in areas of lower fiber density. The principal diffusion directions for the two biexponential components and the monoexponential solution were largely the same and in agreement with known fiber tracts. The second and third diffusion eigenvector directions also appeared to be aligned, but they exhibited significant deviations in localized areas. Magn Reson Med 51:321–330, 2004.

Bone marrow changes in adolescent girls with anorexia nervosa

Early osteoporosis is common among adolescent girls with anorexia nervosa (AN) and may result from premature conversion of red (RM) to yellow bone marrow. We performed right knee magnetic resonance imaging (MRI) on a 1.0 T extremity scanner in 20 patients and 20 healthy controls, aged 16.2 ± 1.6 years (mean ± SD). Coronal T1‐weighted (T1W) images and T1 maps were generated from T1 relaxometry images. Blinded radiologists visually assessed RM in the distal femoral and proximal tibial metaphyses in T1W images using a scale of signal intensity from 0 (homogeneous hyperintensity, no RM) to 4 (all dark, complete RM). Subjects with AN exhibited nearly twofold lower metaphyseal RM scores in both the femur (0.64 versus 1.22, p = .03) and tibia (0.54 versus 0.96, p = .08). In relaxometric measurements of four selected regions (femur and tibia amd epiphysis and metaphysis), subjects with AN showed higher mean epiphyseal but lower metaphyseal T1. The net AN‐control difference between epiphysis and metaphysis was 70 ms in the femur (+31 versus −35 ms, p = .02) and of smaller magnitude in the tibia. In relaxometry data from the full width of the femur adjacent to the growth plate, AN subjects showed mean T1 consistently lower than in controls by 30 to 50 ms in virtually every part of the sampling region. These findings suggest that adolescents with AN exhibit premature conversion of hematopoietic to fat cells in the marrow of the peripheral skeleton potentially owing to adipocyte over osteoblast differentiation in the mesenchymal stem cell pool.

Biexponential apparent diffusion coefficient parametrization in adult vs newborn brain

The decay of brain water signal with b-factor in adult and newborn brains has been measured over an extended b-factor range. Measurements of the apparent diffusion coefficient (ADC) decay curves were made at 16 b-factors from 100 to 5000 s/mm(2) along three orthogonal directions using a line scan diffusion imaging (LSDI) sequence to acquire data from 0.09 ml voxels in a mid-brain axial slice. Regions-of-interest (ROIs) in cortical gray (CG) and white matter in the internal capsule (IC) were selected for ADC decay curve analyses using a biexponential fitting model over this extended b-factor range. Measures of the fast and slow ADC component amplitudes and the traces of the fast and slow diffusion coefficients were obtained from CG and IC ROIs in both adults and newborns. The ADC decay curves from the newborn brain regions were found to have a significantly higher fraction of the fast diffusion ADC component than corresponding regions in the adult brain. The results demonstrate that post-natal brain development has a profound affect on the biexponential parameters which characterize the decay of water signal over an extended b-factor range in both gray and white matter.

Efficacy of bevacizumab plus irinotecan in children with recurrent low-grade gliomas—a Pediatric Brain Tumor Consortium study

BACKGROUND A phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in children with recurrent low-grade glioma to measure sustained response and/or stable disease lasting ≥6 months and progression-free survival. METHODS Thirty-five evaluable patients received 2 doses (10 mg/kg each) of single-agent BVZ intravenously 2 weeks apart and then BVZ + CPT-11 every 2 weeks until progressive disease, unacceptable toxicity, or a maximum of 2 years of therapy. Correlative studies included neuroimaging and expression of tumor angiogenic markers (vascular endothelial growth factor [VEGF], VEGF receptor 2, hypoxia-inducible factor 2α, and carbonic anhydrase 9). RESULTS Thirty-five evaluable patients (median age 8.4 y [range, 0.6-17.6]) received a median of 12 courses of BVZ + CPT-11 (range, 2-26). Twenty-nine of 35 patients (83%) received treatment for at least 6 months. Eight patients progressed on treatment at a median time of 5.4 months (range, 1-17.8). Six patients (17.7%) still in follow-up have had stable disease without receiving additional treatment for a median of 40.1 months (range, 30.6-49.3) from initiating therapy. The 6-month and 2-year progression-free survivals were 85.4% (SE ± 5.96%) and 47.8% (SE ± 9.27%), respectively. The commonest toxicities related to BVZ included grades 1-2 hypertension in 24, grades 1-2 fatigue in 23, grades 1-2 epistaxis in 18, and grades 1-4 proteinuria in 15. The median volume of enhancement decreased significantly between baseline and day 15 (P < .0001) and over the duration of treatment (P < .037). CONCLUSION The combination of BVZ + CPT-11 appears to produce sustained disease control in some children with recurrent low-grade gliomas.

MRI as a central component of clinical trials analysis in brainstem glioma: a report from the Pediatric Brain Tumor Consortium (PBTC).

We report MRI findings from 2 pediatric clinical trials of diffuse intrinsic brainstem glioma (BSG) incorporating concurrent radiation therapy (RT) with molecularly targeted agents (gefitinib and tipifarnib). We determined associations of MRI variables with progression-free survival and overall survival and investigated effects of treatment on these variables. MRI (including diffusion and perfusion) was done before treatment, every 8 weeks (first year), every 12 weeks (thereafter), and at the end of treatment or disease progression. Reduced tumor volume (P < .0001) and tumor diffusion values (P <.0001) were apparent on the first post-RT/drug studies. Decreases in tumor volume correlated with pre-RT volume (P < .0001) and pre-RT diffusion values (P < .0001); larger decreases were noted for tumors with higher volumes and diffusion values. Patients with larger pre-RT tumors had longer progression-free survival (P < .0001). Patients with ≥ 25% decrease in tumor volume and diffusion values after RT had longer progression-free survival (P = .028) and overall survival (P = .0009). Enhancement at baseline and over time was significantly associated with shorter survival. Tumor diffusion values with baseline enhancement were significantly lower than those without (P = .0002). RT of BSG is associated with decreased tumor volume and intralesional diffusion values; patients with ≥ 25% decrease in values post-RT had relatively longer survival intervals, apparently providing an early imaging-based surrogate for relative outcomes. Patients with larger tumors and greater decreases in tumor volume and diffusion values had longer survival intervals. Tumor enhancement was associated with shorter survival, lower tumor diffusion values (increased cellularity), and a smaller drop in diffusion values after RT (P = .006). These associations justify continued investigation in other large clinical trials of brainstem glioma patients.

White matter microstructure and cognition in adolescents with congenital heart disease.

OBJECTIVE To describe the relationship between altered white matter microstructure and neurodevelopment in children with dextro-transposition of the great arteries (d-TGA). STUDY DESIGN We report correlations between regional white matter microstructure as measured by fractional anisotropy (FA) and cognitive outcome in a homogeneous group of adolescents with d-TGA. Subjects with d-TGA (n = 49) and controls (n = 29) underwent diffusion tensor imaging and neurocognitive testing. In the group with d-TGA, we correlated neurocognitive scores with FA in 14 composite regions of interest in which subjects with d-TGA had lower FA than controls. RESULTS Among the patients with d-TGA, mathematics achievement correlated with left parietal FA (r = 0.39; P = .006), inattention/hyperactivity symptoms correlated with right precentral FA (r = -0.39; P = .006) and left parietal FA (r = -0.30; P = .04), executive function correlated with right precentral FA (r = -0.30; P = .04), and visual-spatial skills correlated with right frontal FA (r = 0.30; P = .04). We also found an unanticipated correlation between memory and right posterior limb of the internal capsule FA (r = 0.29; P = .047). CONCLUSION Within the group with d-TGA, regions of reduced white matter microstructure are associated with cognitive performance in a pattern similar to that seen in healthy adolescents and adults. Diminished white matter microstructure may contribute to cognitive compromise in adolescents who underwent open-heart surgery in infancy.

Adolescents with D-transposition of the great arteries repaired in early infancy demonstrate reduced white matter microstructure associated with clinical risk factors.

OBJECTIVE Our objective was to use diffusion tensor imaging (DTI) to compare white matter microstructure in adolescents with D-transposition of the great arteries (D-TGA) who underwent the arterial switch operation in early infancy with typically developing control adolescents. We also examined correlates between patient demographic and medical risk factors and white matter as assessed by regional fractional anisotropy (FA) values. METHODS We used with magnetic resonance imaging (MRI) to study 49 adolescents with D-TGA and 29 control adolescents. MRI data, including whole brain DTI and conventional anatomic MRI, were acquired from each subject. Each subjects data were analyzed using random effects analysis to evaluate regional white matter differences in FA between D-TGA and control adolescents. RESULTS While multifocal punctate MRI hypointensities on T1-weighted (T1W) imaging suggestive of mineralization were found, other evidence of gross white matter injury was absent. Eighteen discrete regions of significantly reduced FA in D-TGA adolescents compared with controls were observed in deep white matter of cerebral hemispheres, cerebellum, and midbrain. Among D-TGA adolescents, lower FA correlated with younger gestational age, shorter duration of intraoperative cooling, higher intraoperative minimum tympanic temperature, longer intensive care unit stay after repair, and greater total number of open cardiac operations. CONCLUSIONS Despite scant white matter injury evident on conventional brain MRI, adolescents with D-TGA repaired in infancy demonstrate significant white matter FA reduction that may relate to their reported neurocognitive deficits. Among adolescents with D-TGA, FA values are associated with patient and perioperative factors, some of which are modifiable.

Prolonged T *2 values in newborn versus adult brain: Implications for fMRI studies of newborns

The neonatal brain possesses higher water content, lower macromolecular concentration, and reduced synaptic density than is found in the brain of a 1‐year‐old child. Changes in MRI characteristics of brain such as relaxation times accompany rapid changes in brain during early postnatal development. It was hypothesized that T  *2 values found in newborns would be significantly higher than those found in 9‐month‐old children and adults as measured at 1.5 T. Spoiled gradient echo measurements of T  *2 within the brains of newborns, 9‐month‐olds, and adults confirmed this hypothesis. The results have implications with regard to functional MRI studies in newborns since, in general, BOLD signal optimization is achieved when echo times TE are set equal to the T  *2 values of the tissue of interest. Since significantly longer T  *2 values are found in newborns, it is suggested that the TE values employed for fMRI studies of newborns should be increased to maximize BOLD signal intensity changes and improve the overall reliability of fMRI results in newborns. Magn Reson Med 51:1287–1291, 2004.

Lack of efficacy of bevacizumab + irinotecan in cases of pediatric recurrent ependymoma--a Pediatric Brain Tumor Consortium study.

A phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in cases of pediatric recurrent ependymoma (EPN) to estimate sustained objective response rate and progression-free survival (PFS). Eligible patients received 2 doses of single-agent BVZ intravenously (10 mg/kg) 2 weeks apart and then BVZ + CPT-11 every 2 weeks until progressive disease, unacceptable toxicity, or a maximum of 2 years of therapy. Correlative studies included diffusion-weighted and T1 dynamic contrast enhanced permeability imaging and tumor immunohistochemistry for vascular endothelial growth factor (VEGF)-A and -B, hypoxia inducible factor-2α, VEGF receptor (R)-2, and carbonic anhydrase (CA)-9. Thirteen evaluable patients received a median of 3 courses (range, 2-12) of BVZ + CPT-11. No sustained response was observed in any patient. Median time to progression in 10 patients was 2.2 months (range, 1.9-6.3). Two patients had stable disease for 10 months and 12 months, respectively. Six-month PFS was 25.7% (SE = 11.1%). Grades I-III toxicities related to BVZ treatment included fatigue in 4 patients, systemic hypertension in 2, epistaxis in 1, headache in 1, and avascular necrosis of bone in 1. Although there was a decrease in the mean diffusion ratio following 2 doses of BVZ, it did not correlate with PFS. BVZ + CPT-11 was well tolerated but had minimal efficacy in cases of recurrent EPN.