Single Low-Dose Targeted Bevacizumab Infusion in Adult Patients with Steroid-Refractory Radiation Necrosis of the Brain: A Phase II Open-Label Prospective Clinical Trial

OBJECTIVE There is an unmet need for safe and rapidly effective therapies for refractory brain radiation necrosis (RN). The aim of this prospective single-arm phase II trial was to evaluate the safety and efficacy of a single low-dose targeted bevacizumab infusion after blood-brain barrier disruption (BBBD) in adult patients with steroid-refractory brain RN. METHODS Ten adults with steroid-refractory, imaging-confirmed brain RN were enrolled between November 2016 and January 2018 and followed for 12 months after treatment. Bevacizumab 2.5 mg/kg was administered as a one-time targeted intra-arterial infusion immediately after BBBD. Primary outcomes included safety and \u3e 25% decrease in lesion volume. Images were analyzed by a board-certified neuroradiologist blinded to pretrial diagnosis and treatment status. Secondary outcomes included changes in headache, steroid use, and functional status and absence of neurocognitive sequelae. Comparisons were analyzed using the Fisher exact test, Mann-Whitney U-test, linear mixed models, Wilcoxon signed-rank test, and repeated-measures 1-way ANOVA. RESULTS Ten adults (mean ± SD [range] age 35 ± 15 [22-62] years) participated in this study. No patients died or exhibited serious adverse effects of systemic bevacizumab. At 3 months, 80% (95% CI 44%-98%) and 90% (95% CI 56%-100%) of patients demonstrated \u3e 25% decrease in RN and vasogenic edema volume, respectively. At 12 months, RN volume decreased by 74% (median [range] 76% [53%-96%], p = 0.012), edema volume decreased by 50% (median [range] 70% [-11% to 83%], p = 0.086), and headache decreased by 84% (median [range] 92% [58%-100%], p = 0.022) among the 8 patients without RN recurrence. Only 1 (10%) patient was steroid dependent at the end of the trial. Scores on 12 of 16 (75%) neurocognitive indices increased, thereby supporting a pattern of cerebral white matter recovery. Two (20%) patients exhibited RN recurrence that required further treatment at 10 and 11 months, respectively, after bevacizumab infusion. CONCLUSIONS For the first time, to the authors\u27 knowledge, the authors demonstrated that a single low-dose targeted bevacizumab infusion resulted in durable clinical and imaging improvements in 80% of patients at 12 months after treatment without adverse events attributed to bevacizumab alone. These findings highlight that targeted bevacizumab may be an efficient one-time treatment for adults with brain RN. Further confirmation with a randomized controlled trial is needed to compare the intra-arterial approach with the conventional multicycle intravenous regimen

Origins of Spatial Working Memory Deficits in Schizophrenia: An Event-Related fMRI and Near-Infrared Spectroscopy Study

Abnormal prefrontal functioning plays a central role in the working memory (WM) deficits of schizophrenic patients, but the nature of the relationship between WM and prefrontal activation remains undetermined. Using two functional neuroimaging methods, we investigated the neural correlates of remembering and forgetting in schizophrenic and healthy participants. We focused on the brain activation during WM maintenance phase with event-related functional magnetic resonance imaging (fMRI). We also examined oxygenated hemoglobin changes in relation to memory performance with the near-infrared spectroscopy (NIRS) using the same spatial WM task. Distinct types of correct and error trials were segregated for analysis. fMRI data indicated that prefrontal activation was increased during WM maintenance on correct trials in both schizophrenic and healthy subjects. However, a significant difference was observed in the functional asymmetry of frontal activation pattern. Healthy subjects showed increased activation in the right frontal, temporal and cingulate regions. Schizophrenic patients showed greater activation compared with control subjects in left frontal, temporal and parietal regions as well as in right frontal regions. We also observed increased ‘false memory’ errors in schizophrenic patients, associated with increased prefrontal activation and resembling the activation pattern observed on the correct trials. NIRS data replicated the fMRI results. Thus, increased frontal activity was correlated with the accuracy of WM in both healthy control and schizophrenic participants. The major difference between the two groups concerned functional asymmetry; healthy subjects recruited right frontal regions during spatial WM maintenance whereas schizophrenic subjects recruited a wider network in both hemispheres to achieve the same level of memory performance. Increased “false memory” errors and accompanying bilateral prefrontal activation in schizophrenia suggest that the etiology of memory errors must be considered when comparing group performances. Finally, the concordance of fMRI and NIRS data supports NIRS as an alternative functional neuroimaging method for psychiatric research

Prefrontal Contributions to Delayed Spatial and Object Alternation: A Positron Emission Tomography Study

Delayed alternation tasks are frequently used as probes of frontal lobe functioning. To clarify the neural substrates of delayed alternation performance in humans, the authors measured 15 regional cerebral blood flow with H2 O positron emission tomography in healthy subjects as they performed delayed spatial and object alternation. Consistent with the monkey lesion literature, increased dorsolateral prefrontal activity emerged during delayed spatial alternation but not delayed object alternation, whereas orbitofrontal activations emerged in both alternation tasks. The possible cognitive processes contributing to the orbitofrontal and dorsolateral prefrontal involvement in delayed alternation are discussed. Additional activations localized to several nonfrontal regions suggest caution in interpreting alternation deficits in patients as strictly reflecting frontal lobe impairment. Delayed alternation tasks have been widely used as probes of frontal lobe functions in both humans and animals. These tasks require subjects to select one of two objects on each trial, with the correct response correspondin

NIRS data comparing maintenance-related NIRS measurements between the control (CO) and schizophrenic (SZ) groups during the spatial WM task.

<p>(A) Deoxy-Hb data: schizophrenic patients showed greater activity in the left frontal cortex (see the left panel) and the healthy control subjects showed greater activation in the right frontal cortex (see the right panel) on correct trials. (B) Oxy-Hb data: schizophrenic patients showed greater activation in the bilateral frontal cortex on correct trials. (C) Total-Hb data: schizophrenic patients showed greater activation in the bilateral frontal cortex compared with the control subjects on correct trials.</p

Activation maps of the delay-related BOLD data in the frontal cortex during the spatial WM task.

<p>(A) For correct trials, schizophrenic patients (SZ) showed increased activation in the middle frontal gyrus (white arrow) and the superior frontal gyrus (yellow arrow) in the left hemisphere whereas the control group (CO) showed increased activation in the middle frontal gyrus and the superior frontal gyrus in the right hemisphere. (B) This figure shows the % signal change during the spatial WM task in the right MFG and the left MFG for correct trials. In the left MFG, schizophrenic patients showed increased activation during maintenance. (C) Schizophrenic patients showed increased activation in the middle frontal gyrus and the superior frontal gyrus during “false memory” trials.</p

A schematic diagram of the spatial working memory (WM) task.

<p>After the presentation of a fixation point (1000 ms), three targets appeared one after the other for 750 ms each with an interstimulus interval of 250 ms. A delay period of 12 s followed. Then a probe was presented. Participants were asked to decide whether the probe was located in one of the target locations or not. After they made a response, they were asked to rate their confidence level for the response that they had just made.</p