Two patients with residual nonfluent aphasia after ischemic stroke received an intention treatment that was designed to shift intention and language production mechanisms from the frontal lobe of the damaged left hemisphere to the right frontal lobe. Consistent with experimental hypotheses, the first patient showed improvement on the intention treatment but not on a similar attention treatment. In addition, in keeping with experimental hypotheses, the patient showed a shift of activity to right presupplementary motor area and the right lateral frontal lobe from pre- to post-intention treatment functional magnetic resonance imaging (fMRI) of language production. In contrast, the second patient showed improvement on both the intention and attention treatments. During pre-treatment fMRI, she already showed lateralization of intention and language production mechanisms to the right hemisphere that continued into post-intention treatment imaging. From pre- to post-treatment fMRI of language production, both patients demonstrated increased activity in the posterior perisylvian cortex, although this activity was lateralized to left-hemisphere language areas in the second but not the first patient. The fact that the first patient's lesion encompassed almost all of the dominant basal ganglia and thalamus whereas the second patient's lesion spared these structures suggests that the dominant basal ganglia could play a role in spontaneous reorganization of language production functions to the right hemisphere. Implications regarding the theoretical framework for the intention treatment are discussed.

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Pseudoprogression may present as transient new or increasing enhancing lesions that mimic recurrent tumors in treated glioblastoma. The purpose of this study was to examine the utility of dynamic contrast enhanced T1 magnetic resonance imaging (DCE MRI) in differentiating between pseudoprogression and tumor progression and devise a cut-off value sensitive for pseudoprogression. We retrospectively examined 37 patients with glioblastoma treated with radiation and temozolomide after surgical resection that then developed new or increasing enhancing lesion(s) indeterminate for pseudoprogression versus progression. Volumetric plasma volume (Vp) and time-dependent leakage constant (Ktrans) maps were measured for the enhancing lesion and the mean and ninetieth percentile histogram values recorded. Lesion outcome was determined by clinical follow up with pseudoprogression defined as stable disease not requiring new treatment. Statistical analysis was performed with Wilcoxon rank-sum tests. Patients with pseudoprogression (n = 13) had Vp (mean) = 2.4 and Vp (90 %tile) = 3.2; and Ktrans (mean) = 3.5 and Ktrans (90 %tile) = 4.2. Patients with tumor progression (n = 24) had Vp (mean) = 5.3 and Vp (90 %tile) = 6.6; and Ktrans (mean) = 7.4 and Ktrans (90 %tile) = 9.1. Compared with tumor progression, pseudoprogression demonstrated lower Vp perfusion values (p = 0.0002) with a Vp (mean) cutoff <3.7 yielding 85 % sensitivity and 79 % specificity for pseudoprogression. Ktrans (mean) of >3.6 had a 69 % sensitivity and 79 % specificity for disease progression. DCE MRI shows lower plasma volume and time dependent leakage constant values in pseudoprogression than in tumor progression. A cut-off value with high sensitivity for pseudoprogression can be applied to aid in interpretation of DCE MRI.

Background High grade gliomas are associated with a dismal prognosis. Notch inhibition via the gamma-secretase inhibitor RO2929097 has emerged as a potential therapeutic option based on modulation of the cancer-initiating cell (CIS) population and a presumed anti-angiogenic role. Methods In this phase 0/I trial, 21 patients with newly-diagnosed glioblastoma or anaplastic astrocytoma received RO4929097 combined with temozolomide and radiotherapy. In addition to establishing the maximum tolerated dose, the study design enabled exploratory studies evaluating tumor and brain drug penetration and neuro-imaging parameters. We also determined functional effects on the Notch pathway and targeting of CISs through analysis of tumor tissue sampled from areas with and without blood-brain barrier disruption. Finally, recurrent tumors were also sampled and assessed for Notch pathway responses while on treatment. Results Treatment was well tolerated and no dose-limiting toxicities were observed. Immunohistochemistry of treated tumors showed a significant decrease in proliferation and in the expression of the Notch intracellular domain (NICD) by tumor cells and blood vessels. Patient-specific organotypic tumor explants cultures revealed a specific decrease in the CD133+ CIS population upon treatment. Perfusion MRI demonstrated a significant decrease in relative plasma volume after drug exposure. Gene expression data in recurrent tumors suggested low Notch signaling activity, the upregulation of key mesenchymal genes and an increase in VEGF-dependent angiogenic factors. Conclusion The addition of RO4929097 to temozolomide and radiotherapy was well tolerated; the drug has variable blood-brain barrier penetration. Evidence of target modulation was observed, but recurrence occurred, associated with alterations in angiogenesis signaling pathways. Clinicaltrials.gov.NCT01119599

Study Design.This was a retrospective study focusing on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to assess treatment response in patients with spinal metastases.Objective.To demonstrate DCE-MRI changes before and after radiation treatment and correlating with other imaging and clinical findings.Summary of Background Data.Currently, conventional imaging is limited in evaluating early treatment success or failure, which impacts patient care.Methods.Consecutive patients with known spinal metastases underwent DCE-MRI before and after radiotherapy. Perfusion data on 19 lesions were analyzed. Radiotherapy was classified as success (n = 17) or failure (n = 2) on the basis of evidence of tumor contraction (n = 4), negative positron emission tomography (n = 2), or stability for more than 11 months (n = 11). Perfusion parameters blood plasma volume (Vp), time-dependent leakage (Ktrans), area under the curve, and peak enhancement were derived from the signal intensity-time curves and changes in parameter values from pre- to post-treatment were calculated. Curve morphologies were also qualitatively assessed in 13 pre- and 13 post-treatment scans.Results.Vp was the strongest predictor of treatment response (false-positive rate = 9.38 × 10−9 and false-negative rate = 0.055). All successfully treated lesions showed decreases in Vp, and the 2 treatment failures showed drastic increases in Vp. Changes in area under the curve and peak enhancement demonstrated similar relationships to the observed treatment response, whereas changes in Ktrans showed no significant relationship. Signal intensity curve morphologies also demonstrated specificity for active disease (11 of 13) and treated disease (8 of 13).Conclusion.Changes in perfusion, particularly Vp, reflect tumor responses to radiotherapy in spinal bone metastases. These changes were able to predict positive outcomes earlier than 6 months after treatment in 16 of 17 tumors. The ability of DCE-MRI to detect early treatment response has the potential to improve patient care and outcome.