Upcoming Trial Research Articles

Exception from informed consent for emergency research: consulting the trauma community.

Research investigating the resuscitation and management of unstable trauma patients is necessary to improve care and save lives. Because informed consent for research is impossible in emergencies, the Federal Drug Administration has established an Exception from Informed Consent (EFIC) Policy that mandates "community consultation" as a means of protecting patient autonomy. We hypothesized that the trauma community represents a heterogeneous population whose attitudes regarding EFIC and willingness to participate in emergency research are influenced by status as a patient, family, or geographic community member. In the context of an upcoming trial, trauma patients as well as family and community members were asked to rank statements regarding EFIC and willingness to participate in emergency research using a 5-point Likert-type scale. Higher total scores reflected a more positive attitude regarding EFIC (range, 4-20; neutral = 12) and willingness (range, 21-105, neutral = 63). The influence of demographics, education, and interpersonal violence were evaluated by Kruskal-Wallis and Mann-Whitney U-tests (p < 0.05). Overall, the 309 participants (trauma patients, n = 172; family, n = 73; community, n = 64) were positive about EFIC (median, 16; interquartile range, [IQR], 14-18) and demonstrated high willingness scores (median, 82; IQR, 76-88.5). EFIC and willingness were not influenced by age, sex, race, or education. Victims of interpersonal violence and their family members had lower EFIC scores than those with other mechanisms (median [IQR], 16 [14-18] vs. 16 [13-16]; p = 0.04) but similar willingness. Although EFIC scores were similar between groups, trauma patients had significantly lower willingness than family (median [IQR], 74 [68-77] vs. 77 [70-85]; p = 0.03) or community members (median [IQR], 76 [70-84]; p = 0.01). Trauma patients, families, and the geographic community expressed a high degree of support for EFIC and willingness to participate in emergency research, although support was influenced by injury mechanism and group status. Consultation efforts for emergency research should extend beyond the geographic community to include trauma victims and their families. Epidemiologic, level III.

1173P - A Highly Sensitive Immunohistochemical Assay to Detect Braf V600E Mutations in Patients with Colorectal Cancer

ABSTRACT Background The BRAF V600E mutation is a well-validated negative prognostic biomarker in metastatic colorectal cancer (mCRC), and is a highly attractive drug target. Barriers to the development of agents targeting BRAF V600E in mCRC are the low rate of mutations (approximately 10%) and reliance on to sequencing-based technologies, which are not routinely available outside of large cancer centres. A simple immunohistochemistry (IHC) test, more suited to routine pathology practice, would provide much broader access to patient (pt) identification, and would also enable studies of tumor heterogeneity. Aims: To validate an IHC-based method of detecting the BRAF V600E mutation in a large cohort of community-based CRC patients. Methods Tissue microarrays, comprising matched normal and tumor paraffin embedded tissue samples obtained from colectomy specimens from a community cohort of 505 pts with stage I–IV CRC, were tested with 2 antibodies (Ab): pBR for total BRAF and VE1 for BRAF V600E, using the Ventana UltraView and OptiView kits, respectively. IHC was assessed independently by 2 blinded pathologists, and results compared to BRAF V600E status determined by Sanger sequencing (SS). pBR negative samples were considered non - evaluable. Nine discordant cases were re-tested with a BRAF V600E SNaPshot assay. Results Demographic features were evenly matched. SS was evaluable in 504/505; IHC in 477/505; with both evaluable in 476/505 pts. 56/476 (11.8%) pts had V600E mutations detected by SS, 65/476 (13.7%) by IHC. The positive predictive value was 84.6% (55/65). 1 pt was negative by IHC and positive on SS and SNaPshot; resulting in a negative predictive value of 99.8% (410/411 cases). There was 100% concordance between SS and SNaPshot. Further validation is ongoing, and outcome data will be available at the time of presentation. Conclusions We have conducted a comprehensive analytical and clinical validation and feasibility analysis of an IHC-based method to detect the BRAF V600E mutation in a large community-based population of pts with CRC. Shown to be highly sensitive, we are planning to adopt this approach as our initial screening step in an upcoming prospective combination trial targeting BRAF V600E in pts with mCRC. Disclosure J. Desai: Research Support: Roche, Ventana Medical Systems, A. Muranyi: Employee: Ventana Medical Systems, K. Shanmugam: Employee and Shareholder, Ventana Medical Systems, T. Grogan: Shareholder and Chief Scientific Officer, Ventana Medical Systems, P. Gibbs: Research Support, Ventana Medical Systems, P. Waring: Research Support: Ventana Medical Systems, All other authors have declared no conflicts of interest.

Q18 Music therapy as a method to improve the quality of life of patients with Huntington's Disease: preliminary findings

IntroductionSince there is no cure for HD all treatment is directed to improve quality of life. One barely recognised non-drug therapy is music therapy. A focus group was installed with...

Hippocampal episode fields develop with learning

Several recent studies have shown that hippocampal neurons fire during the delay period in between trials and that these firing patterns differ when different behaviors are required, suggesting that the neuronal responses may be involved in maintaining the memories needed for the upcoming trial. In particular, one study found that hippocampal neurons reliably fired at particular times, referred to as "episode fields" (EFs), during the delay period of a spatial alternation task (Pastalkova et al. (2008) Science 321:1322-1327). The firing of these neurons resulted in distinct sequential firing patterns on left and right turn trials, and these firing patterns could be used to predict the upcoming behavioral response. In this study, we examined neuronal firing during the delay period of a hippocampus-dependent plus maze task, which involved learning to approach two different reward locations (east and west), and we examined the development of these firing patterns with learning. As in the previous study, hippocampal neurons exhibited discrete periods of elevated firing during the delay (EFs) and the firing patterns were distinct on the east and west trials. Moreover, these firing patterns emerged and began to differentiate the east and west conditions during the first training session and continued to develop as the rats learned the task. The finding of similar firing patterns in different tasks suggests that the EFs are a robust phenomenon, which may occur whenever subjects must maintain distinct memory representations during a delay period. Additionally, in the previous study (Pastalkova et al. (2008) Science 321:1322-1327), the distinct firing patterns could have been due to the differing goal locations, behavioral responses (left or right turns), or trajectories. In this study, neuronal firing varied with the goal location regardless of the trajectories or responses, suggesting that the firing patterns encode the behavioral context rather than specific behaviors.

Optimizing Patient Positioning for Intensity Modulated Radiation Therapy in Hippocampal-Sparing Whole Brain Radiation Therapy

To determine the optimal patient position, using an inclined headboard, for treatment planning of hippocampal-sparing whole brain radiation therapy (WBRT) using intensity modulated radiation therapy (IMRT). Sparing the hippocampus during whole brain radiation therapy offers potential neurocognitive benefits over traditional WBRT. However, previously reported IMRT plans use multiple non-coplanar beams for treatment delivery. Given the possible widespread use of IMRT for WBRT, including an upcoming RTOG trial, an optimized coplanar IMRT template for hippocampal-sparing WBRT would assist in clinical workflow and also help minimize costs. A variable angle, inclined board with the ability to mount an Aquaplast mask was utilized for patient positioning. An anthropomorphic phantom underwent CT simulation at 0, 15, 30, and 40 degree angles. Contours of the brain, lenses of the eyes and hippocampus were generated and used as goal structures for IMRT planning. IMRT goals were designed to achieve target PTV coverage while maintaining a hippocampal D100% ≤ 9 Gy and maximum hippocampal dose ≤ 16 Gy. Planning was initially performed on the 30 degree data set using a coplanar beam arrangement to deliver 30 Gy in 10 fractions. The plan was optimized and then applied to the other head angles. Dose-volume histograms were reviewed with attention paid to D100%, maximum and mean dose to the hippocampus as well as the dose to the lenses. Volumes for the hippocampus, hippocampal avoidance region and whole brain were 1.07 cm3, 12.48 cm3 and 1185.1 cm3 respectively. The hippocampal avoidance region occupied 1.05% of the whole brain planning volume. For the 30 degree head angle, a 7 field IMRT plan utilizing a coplanar beam arrangement was generated sparing the hippocampus to a maximum dose of 14.67 Gy. D100% of the hippocampus was 7.37 Gy and mean hippocampal dose was 9.34 Gy. Similar values were obtained for the 15 degree head angle. In comparison, for flat head positioning the hippocampal Dmax was 22.91 Gy with a D100% of 9.18 Gy and mean dose of 11.7 Gy. Target coverage and dose homogeneity was comparable to previously published non-coplanar IMRT plans. Compared to conventional supine positioning, the use of an inclined head board at 15 or 30 degrees allows for optimal IMRT planning for a coplanar treatment plan. Acceptable dosimetry can be obtained for coplanar hippocampal-sparing whole brain radiation therapy with the addition of an inclined head board.

On the limits of top-down control of visual selection

In the present study, observers viewed displays in which two equally salient color singletons were simultaneously present. Before each trial, observers received a word cue (e.g., the word red, or green) or a symbolic cue (a circle colored red or green) telling them which color singleton to select on the upcoming trial. Even though many theories of visual search predict that observers should be able to selectively attend the target color singleton, the results of the present study show that observers could not select the target singleton without interference from the irrelevant color singleton. The results indicate that the irrelevant color singleton captured attention. Only when the color of the target singleton remained the same from one trial to the next was selection perfect—an effect that is thought to be the result of passive automatic intertrial priming. The results of the present study demonstrate the limits of top-down attentional control.

TMS of the right angular gyrus modulates priming of pop-out in visual search: combined TMS-ERP evidence

During priming of pop-out, performance at discriminating a pop-out feature target in visual search is affected by whether the target on the previous trial was defined by the same feature as on the upcoming trial. Recent studies suggest that priming of pop-out relies on attentional processes. With the use of simultaneous, combined transcranial magnetic stimulation and event-related potential recording (TMS-ERP), we tested for any critical role of the right angular gyrus (rANG) and left and right frontal eye fields (FEFs)-key attentional sites-in modulating both performance and the ERPs evoked by such visual events. Intertrial TMS trains were applied while participants discriminated the orientation of a color pop-out element in a visual search array. rANG TMS disrupted priming of pop-out, reducing reaction time costs on switch trials and speeding responses when the color of the pop-out target switched. rANG TMS caused a negativity in the ERP elicited in response to the visual stimulus array, starting 210 ms after stimulus onset. Both behavioral and ERP effects were apparent only after rANG TMS, on switch trials, and when the target in the visual search array was presented in the left visual field, with no effects after left or right FEF TMS. These results provide evidence for an attentional reorienting mechanism, which originates in the rANG and is modulated by the implicit memory of the previous trial. The rANG plays a causal role on switch trials during priming of pop-out by interacting with visual processing, particularly in the ipsilateral hemisphere representing the contralateral hemifield.

On the limits of top-down control of visual selection

In the present study, observers viewed displays in which two equally salient color singletons were simultaneously present. Before each trial, observers received a word cue (e.g., the word red, or green) or a symbolic cue (a circle colored red or green) telling them which color singleton to select on the upcoming trial. Even though many theories of visual search predict that observers should be able to selectively attend the target color singleton, the results of the present study show that observers could not select the target singleton without interference from the irrelevant color singleton. The results indicate that the irrelevant color singleton captured attention. Only when the color of the target singleton remained the same from one trial to the next was selection perfect—an effect that is thought to be the result of passive automatic intertrial priming. The results of the present study demonstrate the limits of top-down attentional control.

Simple gaze analysis and special design of a virtual Morris water maze provides a new method for differentiating egocentric and allocentric navigational strategy choice

We present a novel method of combining eye tracking with specially designed virtual environments to provide objective evidence of navigational strategy selection. A simple, inexpensive video camera with an easily built infrared LED array is used to capture eye movements at 60 Hz. Simple algorithms analyze gaze position at the start of each virtual maze trial to identify stimuli used for navigational orientation. To validate the methodology, human participants were tested in two virtual environments which differed with respect to features usable for navigation and which forced participants to use one or another of two well-known navigational strategies. Because the environmental features for the two kinds of navigation were clustered in different regions of the environment (and the video display), a simple analysis of gaze-position during the first (i.e., orienting) second of each trial revealed which features were being attended to, and therefore, which navigational strategy was about to be employed on the upcoming trial.

Neural processing of reward magnitude under varying attentional demands

Central to the organization of behavior is the ability to represent the magnitude of a prospective reward and the costs related to obtaining it. Therein, reward-related neural activations are discounted in dependence of the effort required to resolve a given task. Varying attentional demands of the task might however affect reward-related neural activations. Here we employed fMRI to investigate the neural representation of expected values during a monetary incentive delay task with varying attentional demands. Following a cue, indicating at the same time the difficulty (hard/easy) and the reward magnitude (high/low) of the upcoming trial, subjects performed an attention task and subsequently received feedback about their monetary reward. Consistent with previous results, activity in anterior-cingulate, insular/orbitofrontal and mesolimbic regions co-varied with the anticipated reward-magnitude, but also with the attentional requirements of the task. These activations occurred contingent on action-execution and resembled the response time pattern of the subjects. In contrast, cue-related activations, signaling the forthcoming task-requirements, were only observed within attentional control structures. These results suggest that anticipated reward-magnitude and task-related attentional demands are concurrently processed in partially overlapping neural networks of anterior-cingulate, insular/orbitofrontal, and mesolimbic regions.

Knowing the future: Partial foreknowledge effects on the programming of prosaccades and antisaccades

Foreknowledge about the demands of an upcoming trial may be exploited to optimize behavioural responses. In the current study we systematically investigated the benefits of partial foreknowledge – that is, when some but not all aspects of a future trial are known in advance. For this we used an ocular motor paradigm with horizontal prosaccades and antisaccades. Predictable sequences were used to create three partial foreknowledge conditions: one with foreknowledge about the stimulus location only, one with foreknowledge about the task set only, and one with foreknowledge about the direction of the required response only. These were contrasted with a condition of no-foreknowledge and a condition of complete foreknowledge about all three parameters. The results showed that the three types of foreknowledge affected saccadic efficiency differently. While foreknowledge about stimulus-location had no effect on efficiency, task foreknowledge had some effect and response-foreknowledge was as effective as complete foreknowledge. Foreknowledge effects on switch costs followed a similar pattern in general, but were not specific for switching of the trial attribute for which foreknowledge was available. We conclude that partial foreknowledge has a differential effect on efficiency, most consistent with preparatory activation of a motor schema in advance of the stimulus, with consequent benefits for both switched and repeated trials.

Informative cues attenuate attentional capture by irrelevant distractors

Irrelevant color distractors capture a participant's attention during search for a unique shape. However, this capture may not be a purely bottom-up process. Recent research in our lab (Moher, Egeth, Yantis, and Stuphorn, in preparation) has demonstrated that foreknowledge of the probability that an irrelevant color distractor will appear has an impact on the attentional capture achieved by that specific distractor; expected distractors caused less interference in visual search compared to unexpected distractors in both eye tracking and manual response time data. Recently, we have begun exploring whether giving participants information about the upcoming distractor, such as its location or color, will attenuate the effects of capture. In a series of experiments, participants searched for a unique shape among 8 otherwise homogenous shapes, and there was a color distractor present on half of all trials. Prior to each trial, subjects received one of three different cue types. One cue type was neutral, which contained no information about a distractor on the upcoming trial. A second cue type told participants that there would be a distractor on the upcoming trial. A third cue type told participants either the color of the upcoming distractor (Experiment. 1) or the location of the upcoming distractor (Experiment 2). All cues were 100% predictive. Cues that were informative about the color, location, or even mere presence of an upcoming singleton distractor lead to less interference by that distractor. Previous research has shown that participants can use information about an upcoming target to speed visual search. These results suggest that participants are able to incorporate information about an upcoming irrelevant distractor in order to attenuate the effects of that distractor and thus speed visual search as well.

What is top-down about contingent capture?

In the present study, we explored the mechanisms involved in the contingent capture phenomenon, using a variant of the classic precuing paradigm of Folk, Remington, and Johnston (1992). Rather than keeping the target fixed over a whole block of trials (as has traditionally been done with contingent capture experiments), we encouraged participants to adopt a top-down set before each trial. If top-down attentional set determines which property captures attention, as is claimed by the contingent capture hypothesis, one would expect that only properties that match the top-down set would capture attention. We showed that even though participants knew what the target would be on the upcoming trial, both relevant and irrelevant properties captured attention (Experiment 1). An intertrial analysis (Experiments 1 and 2) showed that previous contingent capture findings may, to a large extent, be explained by intertrial priming. In addition, when participants were further forced into adopting the required top-down set (Experiments 3 and 4), irrelevant cues were suppressed, suggesting that top-down control might operate through disengagement of attention from the location of a property that does not match top-down goals. The present findings suggest that top-down control and intertrial priming make their own distinct contributions to the contingent capture phenomenon.

Re-irradiation of metastatic spinal cord compression: A feasibility study by volumetric-modulated arc radiotherapy for in-field recurrence creating a dosimetric hole on the central canal

When local recurrences arise within an irradiated region involving metastatic spinal cord compression, the dose limit to the spinal cord reduces the chance to re-treat the patient by 3D-conformational RT technique. The possibility of using volumetric modulated arc RT by RapidArc was evaluated for dose sparing at spinal cord level and preserving target coverage. A clinically satisfactory PTV coverage and dose sparing to the spinal cord were obtained. An upcoming trial on patients will provide clinical outcomes.

Rethinking the Pathogenesis of Asthma

Asthma research has focused primarily on allergic pathways on the basis that the majority of asthma is associated with atopy, the recruitment of the Th2-type T cell, the cytokines, and the chemokines that are released on exposure to allergens, and the IgE pathway. However, despite considerable investment by industry, targeting these pathways has not resulted in new treatments being developed beyond blockade of cysteinyl leukotrienes and IgE and improvements in inhaled corticosteroids and beta(2)-adrenoceptor bronchodilators. Increasingly, it is recognized that asthma is a heterogeneous disorder, and while important, allergen sensitization is only one component of the disease, with many other environmental and genetic factors playing a role. In addition, these factors act locally on a susceptible airway epithelium that is both structurally and functionally deficient. It may be worthwhile to focus on increasing the resilience of the airways to environmental insults in addition to improving strategies that modify adaptive immunity or suppress inflammation.

Implementing intentions to drink a carbohydrate-electrolyte solution during exercise

In this study, we examined the effectiveness of a theory-based psychological implementation intention strategy on the volume and frequency of intake of a carbohydrate-electrolyte solution by participants engaged in submaximal exercise. Thirty-five participants were randomly assigned to an implementation intention or control condition. Participants assigned to the implementation intention condition were required to write down when and where they would carry out their intention to drink a sports drink in the upcoming exercise trial. Participants completed self-report measures of intentions, the psychological antecedents of intentions, and past behaviour for sports drink use and physical activity before and after receiving the experimental manipulation. Participants then engaged in a one-hour submaximal exercise trial on a cycle ergometer and had free access to a carbohydrate-electrolyte solution throughout. The frequency and volume of sports drink consumed by participants over the course of the trial was recorded. Participants also provided pre- and post-trial urine samples, which were tested for osmolality. Experimental participants imbibed a significantly greater volume of sports drink and had significantly higher urine osmolality than controls. The intervention had no effects on psychological variables. Results support the use of implementation intentions to effectively promote sports drink intake among sports participants.

Anticipatory reconfiguration elicited by fully and partially informative cues that validly predict a switch in task

Task-switching studies show no behavioral benefit of partially informative cues. However, ERP evidence of an early cue-locked positivity elicited by both fully and partially informative cues suggests that both cues trigger an anticipatory component of task set reconfiguration (Nicholson, Karayanidis, Davies, & Michie, 2006). We examined this apparent discrepancy using a cued-trials task-switching paradigm with three tasks. The ERP finding of an early cue-locked positivity was replicated for both switch-to cues, which validly predicted an upcoming switch trial and specified the new task set, and switch-away cues, which validly predicted an upcoming switch trial but not the new task set. This component was not elicited by a noninformative cue that did not specify whether the task would switch or repeat. Switch-away cues resulted in more accurate but not faster responding than did noninformative cues. Modeling of decision processes confirmed a speed-accuracy trade-off between these conditions and a preparation benefit for both switch-to and switch-away cues. These results indicate that both fully and partially informative cues elicit an early anticipatory component of task set reconfiguration that is reflected in the early cue-locked positivity. We argue that the pattern of results is most consistent with a task set inhibition account of this early anticipatory component of task set reconfiguration.

Dorsolateral prefrontal cortex and Stroop performance: Tackling the lateralization

Neuroscience research has identified the involvement of the dorsolateral prefrontal cortex (DLPFC) in cognitive control. Questions remain, however, about its lateralization correlates during Stroop task performance, an experimental cornerstone on which a large amount of cognitive control research is based. After reviewing the literature, we find that three Stroop variants have been used in an attempt to uncover different aspects of cognitive control related to DLPFC involvement. In sum, rapid and sequential up-regulation of the attentional set seems to be related to the left DLPFC. These attentional adjustments are based on participants' expectancies regarding the conflicting nature of the upcoming trial, and not on the conflict itself. In contrast, the right DLPFC is associated with an overall up-regulation of the attentional set when attentional conflict is experienced.

Convection-Enhanced Drug Delivery of Interleukin-4 Pseudomonas Exotoxin (PRX321): Increased Distribution and Magnetic Resonance Monitoring

Convection-enhanced drug delivery (CED) enables achieving a drug concentration within brain tissue and brain tumors that is orders of magnitude higher than by systemic administration. Previous phase I/II clinical trials using intratumoral convection of interleukin-4 Pseudomonas exotoxin (PRX321) have demonstrated an acceptable safety and toxicity profile with promising signs of therapeutic activity. The present study was designed to assess the distribution efficiency and toxicity of this PRX321 using magnetic resonance imaging (MRI) and to test whether reformulation with increased viscosity could enhance drug distribution. Convection of low- [0.02% human serum albumin (HSA)] and high-viscosity (3% HSA) infusates mixed with gadolinium-diethylenetriamine pentaacetic acid and PRX321 were compared with low- and high-viscosity infusates without the drug, in normal rat brains. MRI was used for assessment of drug distribution and detection of early and late toxicity. Representative brain samples were subjected to histological examination. Distribution volumes calculated from the magnetic resonance images showed that the average distribution of 0.02% HSA was larger than that of 0.02% HSA with PRX321 by a factor of 1.98 (p < 0.02). CED of 3.0% HSA, with or without PRX321, tripled the volume of distribution compared with 0.02% HSA with PRX321 (p < 0.015). No drug-related toxicity was detected. These results suggest that the impeded convection of the PRX321 infusate used in previous clinical trials can be reversed by increasing infusate viscosity and lead to tripling of the volume of distribution. This effect was not associated with any detectable toxicity. A similar capability to reverse impeded convection was also demonstrated in a CED model using acetic acid. These results will be implemented in an upcoming phase IIb PRX321 CED trial with a high-viscosity infusate.

Updating the programming of a precision grip is a function of recent history of available feedback

In a recent study (Whitwell et al. in Exp Brain Res 185:111-119, 2008), we showed that the visuomotor system is "cognitively impenetrable" to the extent that explicit predictive knowledge of the availability of visual feedback on an upcoming trial fails to optimize grasping. The results suggested that the effects of trial history, rather than the anticipatory knowledge of the nature of an upcoming trial, plays the most significant role in how the availability of visual feedback is exploited by the visuomotor system when programming grip aperture (e.g., opening the hand wider when visual feedback is unavailable). Here, we provide direct evidence that trial history indeed plays a critical role in the programming of grip aperture. Twelve individuals grasped objects of three different sizes placed at one of two distances either with or without visual feedback of the hand and object (closed- or open-loop trials, respectively). Runs of four consecutive closed- or open-loop trials were interleaved with sequences of closed and open-loop trials that alternated back and forth from trial to trial. Peak grip aperture (PGA) decreased linearly with successive closed-loop trials and increased linearly with successive open-loop trials. We also compared PGA for trials that were preceded by a run of four consecutive closed- (or open-loop) trials with trials that were preceded by only one closed- (or open-loop) trial. This analysis indicated that consistency in the runs of closed- or open-loop trials significantly reduced the effect of the availability of feedback on grasping in the trial following the run. We conclude that while the margin of error observed in precision grasping is largely a function of the availability of visual feedback on the current trial, it is evidently also a function of the recent history of the availability of visual feedback on previous trials.