Using MRI techniques, we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171-an oral tyrosine kinase inhibitor of VEGF receptors-has rapid onset, is prolonged but reversible, and has the significant clinical benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for as long as four months. Basic FGF, SDF1alpha, and viable circulating endothelial cells (CECs) increased when tumors escaped treatment, and circulating progenitor cells (CPCs) increased when tumors progressed after drug interruption. Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor.

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Recent developments in MRI data acquisition technology are starting to yield images that show anatomical features of the hippocampal formation at an unprecedented level of detail, providing the basis for hippocampal subfield measurement. However, a fundamental bottleneck in MRI studies of the hippocampus at the subfield level is that they currently depend on manual segmentation, a laborious process that severely limits the amount of data that can be analyzed. In this article, we present a computational method for segmenting the hippocampal subfields in ultra-high resolution MRI data in a fully automated fashion. Using Bayesian inference, we use a statistical model of image formation around the hippocampal area to obtain automated segmentations. We validate the proposed technique by comparing its segmentations to corresponding manual delineations in ultra-high resolution MRI scans of 10 individuals, and show that automated volume measurements of the larger subfields correlate well with manual volume estimates. Unlike manual segmentations, our automated technique is fully reproducible, and fast enough to enable routine analysis of the hippocampal subfields in large imaging studies.

The ascending reticular activating system (ARAS) mediates arousal, an essential component of human consciousness. Lesions of the ARAS cause coma, the most severe disorder of consciousness. Because of current methodological limitations, including of postmortem tissue analysis, the neuroanatomic connectivity of the human ARAS is poorly understood. We applied the advanced imaging technique of high angular resolution diffusion imaging (HARDI) to elucidate the structural connectivity of the ARAS in 3 adult human brains, 2 of which were imaged postmortem. HARDI tractography identified the ARAS connectivity previously described in animals and also revealed novel human pathways connecting the brainstem to the thalamus, hypothalamus, and basal forebrain. Each pathway contained different distributions of fiber tracts from known neurotransmitter-specific ARAS nuclei in the brainstem. The histologically guided tractography findings reported here provide initial evidence for human-specific pathways of the ARAS. The unique composition of neurotransmitter-specific fiber tracts within each ARAS pathway suggests structural specializations that subserve the different functional characteristics of human arousal. This ARAS connectivity analysis provides proof of principle that HARDI tractography may impact the study of human consciousness and its disorders, including in neuropathologic studies of patients dying in coma and the persistent vegetative state.

In brain morphometry studies using magnetic resonance imaging, several scans with a range of contrasts are often collected. The images may be locally distorted due to imperfect shimming in regions where magnetic susceptibility changes rapidly, and all scans may not be distorted in the same way. In multispectral studies it is critical that the edges of structures align precisely across all contrasts. The MPRAGE (MPR) sequence has excellent contrast properties for cortical segmentation, while multiecho FLASH (MEF) provides better contrast for segmentation of subcortical structures. Here, a multiecho version of the MPRAGE (MEMPR) is evaluated using SIENA and FreeSurfer. The higher bandwidth of the MEMPR results in reduced distortions that match those of the MEF while the SNR is recovered by combining the echoes. Accurate automatic identification of cortex and thickness estimation is frustrated by the presence of dura adjacent to regions such as the entorhinal cortex. In the typical MPRAGE protocol, dura and cortex are approximately isointense. However, dura has substantially smaller T2* than cortex. This information is represented in the multiple echoes of the MEMPR. An algorithm is described for correcting cortical thickness using T2*. It is shown that with MEMPR, SIENA generates more reliable percentage brain volume changes and FreeSurfer generates more reliable cortical models. The regions where cortical thickness is affected by dura are shown. MEMPR did not substantially improve subcortical segmentations. Since acquisition time is the same for MEMPR as for MPRAGE, and it has better distortion properties and additional T2* information, MEMPR is recommended for morphometry studies.

A number of factors have to be considered for implementing an accurate attenuation correction (AC) in a combined MR-PET scanner. In this work, some of these challenges were investigated and an AC method based entirely on the MR data obtained with a single dedicated sequence was developed and used for neurological studies performed with the MR-PET human brain scanner prototype. Methods The focus was on the bone/air segmentation problem, the bone linear attenuation coefficient selection and the RF coil positioning. The impact of these factors on the PET data quantification was studied in simulations and experimental measurements performed on the combined MR-PET scanner. A novel dual-echo ultra-short echo time (DUTE) MR sequence was proposed for head imaging. Simultaneous MR-PET data were acquired and the PET images reconstructed using the proposed MR-DUTE-based AC method were compared with the PET images reconstructed using a CT-based AC. Results Our data suggest that incorrectly accounting for the bone tissue attenuation can lead to large underestimations (>20%) of the radiotracer concentration in the cortex. Assigning a linear attenuation coefficient of 0.143 or 0.151 cm−1 to bone tissue appears to give the best trade-off between bias and variability in the resulting images. Not identifying the internal air cavities introduces large overestimations (>20%) in adjacent structures. Based on these results, the segmented CT AC method was established as the “silver standard” for the segmented MR-based AC method. Particular to an integrated MR-PET scanner, ignoring the RF coil attenuation can cause large underestimations (i.e. up to 50%) in the reconstructed images. Furthermore, the coil location in the PET field of view has to be accurately known. Good quality bone/air segmentation can be performed using the DUTE data. The PET images obtained using the MR-DUTE- and CT-based AC methods compare favorably in most of the brain structures. Conclusion An MR-DUTE-based AC method was implemented considering all these factors and our preliminary results suggest that this method could potentially be as accurate as the segmented CT method and it could be used for quantitative neurological MR-PET studies.

A B S T R A C T PurposeGlioblastoma is an incurable solid tumor characterized by increased expression of vascular endothelial growth factor (VEGF). We performed a phase II study of cediranib in patients with recurrent glioblastoma. MethodsCediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor, was administered (45 mg/d) until progression or unacceptable toxicity to patients with recurrent glioblastoma. The primary end point was the proportion of patients alive and progression free at 6 months (APF6). We performed magnetic resonance imaging (MRI) and plasma and urinary biomarker evaluations at multiple time points. ResultsThirty-one patients with recurrent glioblastoma were accrued. APF6 after cediranib was 25.8%. Radiographic partial responses were observed by MRI in 17 (56.7%) of 30 evaluable patients using three-dimensional measurements and in eight (27%) of 30 evaluable patients using twodimensional measurements. For the 15 patients who entered the study taking corticosteroids, the dose was reduced (n ϭ 10) or discontinued (n ϭ 5). Toxicities were manageable. Grade 3/4 toxicities included hypertension (four of 31; 12.9%); diarrhea (two of 31; 6.4%); and fatigue (six of 31; 19.4%). Fifteen (48.4%) of 31 patients required at least one dose reduction and 15 patients required temporary drug interruptions due to toxicity. Drug interruptions were not associated with outcome. Changes in plasma placental growth factor, basic fibroblast growth factor, matrix metalloproteinase (MMP) -2, soluble VEGF receptor 1, stromal cell-derived factor-1␣, and soluble Tek/Tie2 receptor and in urinary MMP-9/neutrophil gelatinase-associated lipocalin activity after cediranib were associated with radiographic response or survival. ConclusionCediranib monotherapy for recurrent glioblastoma is associated with encouraging proportions of radiographic response, 6-month progression-free survival, and a steroid-sparing effect with manageable toxicity. We identified early changes in circulating molecules as potential biomarkers of response to cediranib. The efficacy of cediranib and the predictive value of these candidate biomarkers will be explored in prospective trials.