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Hepatic resection is the gold standard treatment for patients affected by liver-limited colorectal metastases. Reports addressing the impact of multidisciplinary team (MDT) evaluation on survival are controversial. The aim of this study was to evaluate the benefit of MDT management in these patients in our Institution experience. The objective of the analysis was to compare survivals of patients managed within our MDT (MDT cohort) to those of patients referred to surgery from other hospitals without MDT discussion (non-MDT cohort). Of the 523 patients, 229 were included in the MDT cohort and 294 in the non-MDT cohort. No difference between the two groups was found in terms of median overall survival (52.5 vs 53.6 months; HR 1.13; 95% CI, 0.88–1.45; p = 0.344). In the MDT cohort there was a higher number of metastases (4.5 vs 2.7; p p p

Knowledge without awareness, or implicit knowledge, influences a variety of behaviors. It is unknown however, whether implicit knowledge of statistical structure informs visual perceptual decisions or whether explicit knowledge of statistical probabilities is required. Here, we measured visual decision-making performance using a novel task in which humans reported the orientation of two differently colored translational Glass patterns; each color associated with different orientation probabilities. The task design allowed us to assess participants’ ability to learn and use a general orientation prior as well as a color specific feature prior. Classifying decision-makers based on a questionnaire revealed that both implicit and explicit learners implemented a general orientation bias by adjusting the starting point of evidence accumulation in the drift diffusion model framework. Explicit learners additionally adjusted the drift rate offset. When subjects implemented a stimulus specific bias, they did so by adjusting primarily the drift rate offset. We conclude that humans can learn priors implicitly for perceptual decision-making and depending on awareness implement the priors using different mechanisms.

The superior colliculus is a conserved sensorimotor structure that integrates visual and other sensory information to drive reflexive behaviors. Although the evidence for this is strong and compelling, a number of experiments reveal a role for the superior colliculus in behaviors usually associated with the cerebral cortex, such as attention and decision-making. Indeed, in addition to collicular outputs targeting brainstem regions controlling movements, the superior colliculus also has ascending projections linking it to forebrain structures including the basal ganglia and amygdala, highlighting the fact that the superior colliculus, with its vast inputs and outputs, can influence processing throughout the neuraxis. Today, modern molecular and genetic methods combined with sophisticated behavioral assessments have the potential to make significant breakthroughs in our understanding of the evolution and conservation of neuronal cell types and circuits in the superior colliculus that give rise to simple and complex behaviors.

International audience; Over the past 10-20 years, neuroscience witnessed an explosion in the use of non-invasive imaging methods, particularly magnetic resonance imaging (MRI), to study brain structure and function. Simultaneously, with access to MRI in many research institutions, MRI has become an indispensable tool for researchers and veterinarians to guide improvements in surgical procedures and implants and thus, experimental as well as clinical outcomes, given that access to MRI also allows for improved diagnosis and monitoring for brain disease. As part of the PRIMEatE Data Exchange, we gathered expert scientists, veterinarians, and clinicians who treat humans, to provide an overview of the use of non-invasive imaging tools, primarily MRI, to enhance experimental and welfare outcomes for laboratory non-human primates engaged in neuroscientific experiments. We aimed to provide guidance for other researchers, scientists and veterinarians in the use of this powerful imaging technology as well as to foster a larger conversation and community of scientists and veterinarians with a shared goal of improving the well-being and experimental outcomes for laboratory animals.

Background: Guidelines recommend a perioperative approach in patients with stage II/III gastric cancer, but in real-life many patients receive immediate surgery followed by adjuvant chemotherapy (aCT). Although histologic subtypes may have different response to CT, no study has explored the influence of histotype on the efficacy of perioperative CT (pCT) or aCT. Materials and methods: The objective of the study was to evaluate the impact of clinicopathological features and histology (intestinal or diffuse) on survival according to strategy (pCT vs. aCT). The primary endpoint was overall survival (OS) and the secondary endpoint was event-free survival (EFS). Results: Out of 203 patients affected by LAGC, 83 received pCT and 120 aCT. At multivariate, histology and LVI in pCT cohort and positive resection margin in the aCT influenced both OS and EFS. No difference in EFS and OS was observed in relation to strategy. However, in the intestinal-type of pCT cohort survival outcomes were significantly higher compared to the aCT cohort, whereas in the diffuse-type were significantly worse in patients receiving pCT compared to those receiving aCT. Conclusions: Although retrospective and small-sized, this study suggests that the benefit of pCT might be limited to the intestinal-type. This hypothesis needs to be confirmed in prospective series.

The zona incerta contains GABAergic neurons that project to the superior colliculus in the cat and rat, suggesting that it plays a role in gaze changes. However, whether this incertal connection represents a general mammalian pattern remains to be determined. We used neuronal tracers to examine the zona incerta connections with the midbrain tectum in the gray squirrel and macaque monkey. Collicular injections in both species revealed that most incertotectal neurons lay in the ventral layer, but anterogradely labeled tectoincertal terminals were found in both the dorsal and ventral layers. In the monkey, injections of the pretectum also produced retrograde labeling, but mainly in the dorsal layer. The dendritic fields of incertotectal and incertopretectal cells were generally contained within the layer inhabited by their somata. The macaque, but not the squirrel, zona incerta extended dorsolaterally, within the external medullary lamina. Zona incerta injections produced retrogradely labeled neurons in the superior colliculus of both species. In the squirrel, most cells inhabited the lower sublamina of the intermediate gray layer, but in the monkey, they were scattered throughout the deeper layers. Labeled cells were present among the pretectal nuclei in both species. Labeled terminals were concentrated in the lower sublamina of the intermediate gray layer of both species, but were dispersed among the pretectal nuclei. In summary, an incertal projection that is concentrated on the collicular motor output layers and that originates in the ventral layer of the ipsilateral zona incerta is a common mammalian feature, suggesting an important role in collicular function.

Simple Summary The global methylation profile of two human metastatic colorectal carcinoma subgroups with significantly different outcomes (primary-resistant versus drug-sensitive tumors) was analyzed and compared with the gene expression and methylation data from The Cancer Genome Atlas COlon ADenocarcinoma (TCGA COAD) metastatic colorectal carcinoma dataset with the aim to identify a prognostic signature of functionally methylated genes. A novel epigenetic eight-gene signature, with hypermethylation of the promoter regions, was identified and validated for its capacity to predict poor outcome, which had a CpG-island methylator phenotype (CIMP)-high status and microsatellite instability (MSI)-like phenotype. Abstract Epigenetics is involved in tumor progression and drug resistance in human colorectal carcinoma (CRC). This study addressed the hypothesis that the DNA methylation profiling may predict the clinical behavior of metastatic CRCs (mCRCs). The global methylation profile of two human mCRC subgroups with significantly different outcome was analyzed and compared with gene expression and methylation data from The Cancer Genome Atlas COlon ADenocarcinoma (TCGA COAD) and the NCBI GENE expression Omnibus repository (GEO) GSE48684 mCRCs datasets to identify a prognostic signature of functionally methylated genes. A novel epigenetic signature of eight hypermethylated genes was characterized that was able to identify mCRCs with poor prognosis, which had a CpG-island methylator phenotype (CIMP)-high and microsatellite instability (MSI)-like phenotype. Interestingly, methylation events were enriched in genes located on the q-arm of chromosomes 13 and 20, two chromosomal regions with gain/loss alterations associated with adenoma-to-carcinoma progression. Finally, the expression of the eight-genes signature and MSI-enriching genes was confirmed in oxaliplatin- and irinotecan-resistant CRC cell lines. These data reveal that the hypermethylation of specific genes may provide prognostic information that is able to identify a subgroup of mCRCs with poor prognosis.

This study was designed to assess the feasibility and safety of a single-step combined therapy using radiofrequency ablation and transarterial chemoembolization (RFA + TACE) in patients with hepatocellular carcinoma (HCC) and uncontrolled coagulopathy. The study also aimed to compare the effectiveness of this approach with TACE alone, performed in a control group.One hundred and forty-three consecutive cirrhotic patients having a single HCC 8 cm were enrolled in this observational prospective single-center study from January 2010 to June 2017 and were divided, according to coagulation tests, into three groups (A: low risk; B: intermediate risk and C: high risk of bleeding). The feasibility and safety of a single-step combined treatment (RFA followed by TACE) were evaluated in terms of technical success rate, periprocedural complications, and laboratory values variations. Tumor response obtained at 1-month CT follow-up for group C was compared with that of control group, composed by 16 matched patients with severe coagulopathy and single HCC 8 cm, who underwent only TACE in a previous period, performed by the same operator.Technical success was achieved in all patients, without any major complications. Minor complications rate was significantly higher in group C after RFA; however, the patients were successfully treated with subsequent TACE therapy, without any differences between pre- and post-procedural laboratory values. One-month complete response rates were similar in all the three groups; however, the response rates of group C were significantly higher as compared to that of the control TACE Group (p .001).The single-step RFA plus TACE therapy allows expansion of the indication for percutaneous thermal ablation, allowing to also include cases previously contraindicated due to the procedural high-risk of complications associated with bleeding, thus improving short-term patient outcome.

Both cognitive and motor symptoms in people with Parkinson’s disease (PD) arise from either too little or too much dopamine (DA). Akinesia stems from DA neuronal cell loss, and dyskinesia often stems from an overdose of DA medication. Cognitive behaviors typically associated with frontal cortical function, such as working memory and task switching, are also affected by too little or too much DA in PD. Whether motor and cognitive circuits overlap in PD is unknown. In this article, we show that whereas motor performance improves in people with PD when on dopaminergic medication compared with off medication, perceptual decision-making based on previously learned information (priors) remains impaired whether on or off medications. To rule out effects of long-term DA treatment and dopaminergic neuronal loss such as occur in PD, we also tested a group of people with dopa-unresponsive focal dystonia, a disease that involves the basal ganglia, like PD, but has motor symptoms that are insensitive to dopamine treatment and is not thought to involve frontal cortical DA circuits, unlike PD. We found that people with focal dystonia showed intact perceptual decision-making performance but impaired use of priors in perceptual decision-making, similar to people with PD. Together, the results show a dissociation between motor and cognitive performance in people with PD and reveal a novel cognitive impairment, independent of sensory and motor impairment, in people with focal dystonia. The combined results from people with PD and people with focal dystonia provide mechanistic insights into the role of basal ganglia non-dopaminergic circuits in perceptual decision-making based on priors.

Recent studies suggest that neurons in sensorimotor circuits involved in perceptual decision-making also play a role in decision confidence. In these studies, confidence is often considered to be an optimal readout of the probability that a decision is correct. However, the information leading to decision accuracy and the report of confidence often co-varied, leaving open the possibility that there are actually two dissociable signal types in the brain: signals that correlate with decision accuracy (optimal confidence) and signals that correlate with subjects’ behavioral reports of confidence (subjective confidence). We recorded neuronal activity from a sensorimotor decision area, the superior colliculus (SC) of monkeys, while they performed two different tasks. In our first task, decision accuracy and confidence co-varied, as in previous studies. In our second task, we implemented a novel motion discrimination task with stimuli that were matched for decision accuracy but produced different levels of confidence as reflected by behavioral reports. We used a multivariate decoder to predict monkeys’ choices from neuronal population activity. As in previous studies on perceptual decision-making mechanisms, we found that neuronal decoding performance increased as decision accuracy increased. However, when decision accuracy was matched, performance of the decoder was similar between high and low subjective confidence conditions. These results show that the SC likely signals optimal decision confidence similar to previously reported cortical mechanisms, but is unlikely to play a critical role in subjective confidence. The results also motivate future investigations to determine where in the brain signals related to subjective confidence reside.Significance StatementConfidence is thought to reflect the rational or optimal belief concerning one’s choice accuracy. Here, we introduce a novel version of the dot-motion discrimination task with stimulus conditions that produce similar accuracy but different subjective behavioral reports of confidence. We decoded decision performance of this task from neuronal signals in the superior colliculus (SC), a subcortical region involved in decision-making. We found that SC activity signaled a perceptual decision for visual stimuli, with the strength of this activity reflecting decision accuracy, but not the subjective level of confidence as reflected by behavioral reports. These results demonstrate an important role for the SC in perceptual decision-making and challenge current ideas about how to measure subjective confidence in monkeys and humans.

Current dominant views hold that perceptual confidence reflects the probability that a decision is correct. Although these views have enjoyed some empirical support, recent behavioral results indicate that confidence and the probability of being correct can be dissociated. An alternative hypothesis suggests that confidence instead reflects the magnitude of evidence in favor of a decision while being relatively insensitive to the evidence opposing the decision. We considered how this alternative hypothesis might be biologically instantiated by developing a simple leaky competing accumulator neural network model incorporating a known property of sensory neurons: tuned normalization. The key idea of the model is that each accumulator neuron’s normalization ‘tuning’ dictates its contribution to perceptual decisions versus confidence judgments. We demonstrate that this biologically plausible model can account for several counterintuitive findings reported in the literature, where confidence and decision accuracy were shown to dissociate -- and that the differential contribution a neuron makes to decisions versus confidence judgments based on its normalization tuning is vital to capturing some of these effects. One critical prediction of the model is that systematic variability in normalization tuning exists not only in sensory cortices but also in the decision-making circuitry. We tested and validated this prediction in macaque superior colliculus (SC; a region implicated in decision-making). The confirmation of this novel prediction provides direct support for our model. These findings suggest that the brain has developed and implements this alternative, heuristic theory of perceptual confidence computation by capitalizing on the diversity of neural resources available.SignificanceThe dominant view of perceptual confidence proposes that confidence optimally reflects the probability that a decision is correct. But recent empirical evidence suggests that perceptual confidence exhibits a suboptimal ‘confirmation bias’, just as in human decision-making in general. We tested how this ‘bias’ might be neurally implemented by building a biologically plausible neural network model, and showed that the ‘bias’ emerges when each neuron’s degree of divisive normalization dictates how it drives decisions versus confidence judgments. We confirmed the model’s biological substrate using electrophysiological recordings in monkeys. These results challenge the dominant model, suggesting that the brain instead capitalizes on the diversity of available machinery (i.e., neuronal resources) to implementheuristic-- not optimal -- strategies to compute subjective confidence.

3558 Background: Target therapies and new surgical strategies deeply modify the history of CCLM patients (pts). Several prognostic scoring systems have been developed but no one is able to identify pts who should be excluded from a potentially useless surgery. Currently research is committed in identifying early biomarkers able to discern pts who could benefit from an aggressive approach. Exosomes are arising as promising biomarkers in cancer. The aim of this pivotal study was to analyze the association among exosome levels during CCLM-pts treatment, clinical outcomes and the KRAS status. Methods: We enrolled 22 pts with CCLM candidate to preoperative chemotherapy (pCT) and subsequent liver surgery. A blood sample was collected before pCT, after surgery, monthly during follow-up and at progression (PD). Exosomes were isolated by ultracentrifugation and characterized by standard methods. Exosomes concentration was assessed by Bradford assay. We adopted ddPCR™ KRAS G12/G13 Screening Kit to evaluate the KRAS status in exosomal DNA (e-DNA). Results: 22 CCLM pts received pCT and underwent liver surgery: 5 major hepatectomies and 17 multiple liver resections. Changes in exosomes plasma levels were found to correlate with each treatment step,resulting reduced after pCT and surgery and increased at PD, respectively (p = 0.0026). Pts with higher baseline exosome levels experimented shorter PFS than those with lower levels (p = 0.0033 HR 0.2). No association was found between exosome levels after liver surgery and disease free interval nor overall survival. KRAS status on e-DNA was evaluated on 10 pts in baseline, in pCT, after surgery, and in PD samples. In 8 out of 10 pts e-DNA displayed the same mutational status than the one detected on tumor DNA. Changes in e-DNA KRAS copies were found statistically significant in pCT vs surgery and pCT vs PD (p = 0.039; p = 0.04). Conclusions: Our study suggests a prognostic role of exosome levels in CCLM pts. Moreover, we showed that KRAS mutational status could be monitored during the post-surgery follow up by analyzing e-DNA. Overall, our data confirm the potential role of exosomes in liquid biopsy tool to monitor molecular changes during the treatment of CCLM pts.

3556 Background: The optimal treatment for mCRC beyond 2nd line is still questioned. Recently, REG and TAS-102 showed to improve survival compared to BSC. While in real-world practice CTr/r is often considered in this setting, supporting evidences are limited. In absence of studies comparing all these strategies, we aimed to compare the prognostic performance of CTr/r, REG and TAS-102 in mCRC treated beyond 2nd line. Methods: mCRC pts progressing after at least 2 lines of CT, treated with CTr/r, REG or TAS-102 between Jan-10 and Jan-19 were considered eligible. The primary endpoint was OS; secondary endpoints were PFS and RR. Cox’s proportional hazard models for survivals were estimated. A propensity score (PS) adjustment for baseline characteristics was further accomplished for survival analysis. Results: The clinical data of 341 pts (CTr/r 133, REG 150, TAS-102 58) were retrospectively collected. At multivariate analysis type of treatment, ECOG PS, number of metastatic sites and treatment line independently correlated with OS ( p < .001, p .001, p < .001 and p .029, respectively). The mOS was 18.5 (95% CI, 14.3–22.7), 6 (95% CI, 5.6–9.5) and 7.6 months (95%CI, 5.6–9.5), for CTr/r, REG and TAS-102 group, respectively (log-rank p < .0001). mOS was significantly longer for pts receiving CTr/r than for those treated with REG/TAS-102 (15.8 vs 7.1 months; adjusted HR 1.96, 95% CI 1.44-2.66; p < .0001) at the PS analysis, adjusted for ECOG PS, number of metastatic sites and treatment line; 2-yrs OS was 34% and 11.6% for CTr/r and REG/TAS-102, respectively. PFS was significantly longer for pts receiving CTr/r than for those treated with REG/TAS-102 (5.5 vs 3.9 months; HR 1.45, 95% CI 1.11-1.91; p .006) at the PS analysis. Accordingly, RR was higher in pts receiving CTr/r compared to REG/TAS-102 (29.0 vs 1.5%; Chi-square p < .00001). Conclusions: Our analysis, although underpowered, generates the hypothesis of a superiority of CTr/r in comparison to REG or TAS-102, in both efficacy and activity. Given the retrospective nature of our analysis, and the potential role of selection bias in treatment assignment, a prospective validation is mandatory.

e15038 Background: Right- (R) and left-sided (L) mCRCs exhibit different clinical and molecular features. Several retrospective analyses showed that the survival benefit of anti-EGFR-based tx is limited to RAS/BRAF wt L-sided mCRC pts, with a larger effect in the first-line setting. Few data are available concerning the anti-EGFR efficacy according to TL in 2nd and following lines. Methods: Pts affected by RAS/BRAF wt mCRC treated at our Institution with anti-EGFR-based tx in 2nd and following lines were retrospectively collected. The objective of the analysis was to compare tx activity and efficacy according to TL. Primary endpoint was overall survival (OS); secondary endpoints were progression free survival (PFS) and response rate (RR). Results: A total of 47 RAS/BRAF wt mCRC pts treated with an anti-EGFR-based tx in 2nd and following lines were identified. Of those, 32 (68%) were L-sided and 15 (32%) R-sided, respectively. Pts (age, gender, PS ECOG) and tumor (number of metastatic sites) characteristics and number of tx lines were well balanced between the two 21 pts received anti-EGFR alone, 26 pts anti-EGFR plus CT. mOS was 22.3 in L-sided and 7.3 months in R-sided group (HR 2.3, 95%CI 1.02-5.14, p = 0.04). At multivariate analysis TL and PS ECOG independently correlated with OS ( p = 0.02 and p =0.0089). mPFS was 8.4 and 3.9 months in pts with L-sided and R-sided tumor, respectively (HR 1.3; 95%CI 0.64-2.80, p =0.43). RR was higher in L-sided compared to R-sided tumor (37.5 vs 13.3) ( p= 0.09). Conclusions: Our analysis, although limited by the small sample and by its retrospective nature, indicates a better OS in L-sided compared to R-sided tumors treated with anti-EGFR-based tx in 2nd and following lines. A prospective validation is warranted.

44 Background: The emerging role of immunotherapy (IT) in cancer treatments has increased the research about tumor microenvironment (TME), tumor infiltrating lymphocytes (TILs) function and their TME regulation. Nowadays ongoing trial are showing conflicting preliminary data about the efficacy of IT in advanced gastric cancer (GC). Therefore, we performed this exploratory analysis to evaluate the correlation between histology, TILs density (reported as CD4/CD8 tissue ratio), neutrophil-lymphocytes ratio (NLR) and response outcome in GC patients who underwent cytotoxic neoadjuvant treatment (NAD). Methods: CD4+ and CD8+ expression was assessed by immunohistochemistry (IHC) in pre-NAD biopsies. NLR was calculated on baseline complete blood count. A cut-off value to define low or high NLR has been selected on 3.0, based on literature data. X2 test was used to explore the correlation between histology, CD4/CD8 ratio, NLR and response. Results: We analyzed 10 diffuse and 10 intestinal GC histotypes. In the intestinal-type CD4/CD8 ratio was lower (ratio range 1:15 - 1:20) with a predominant count of CD8+ suggesting a hot and inflamed TME compared to the diffuse cohort (ratio range 1:3 -1:5) where both CD8+ and CD4+ density was lower (p=0.03). Baseline NLR was calculated in 18 out of 20 pts. All intestinal GCs showed a low NLR (

A large body of work spanning 25+ years provides compelling evidence for the involvement of the basal ganglia-superior colliculus pathway in the initiation of rapid, orienting movements of the eyes, called saccades. The role of this pathway in saccade control is similar to the role of the basal ganglia-thalamic pathway in the control of skeletal movement: a transient cessation in tonic inhibition supplied by the basal ganglia to motor structures releases movements via the direct pathway whereas a transient increase in inhibition by the basal ganglia to motor structures prevents movements via the indirect pathway. In parallel with recent advances in the study and treatment of patients with basal ganglia disease and in animal experiments in the skeletal motor system, the results of studies exploring the role of the basal ganglia-superior colliculus pathway in saccades highlight the need for a revisiting of our understanding of the role of this pathway in saccades. The discovery of many different response profiles of neurons in the substantia nigra pars reticulata of the basal ganglia and in the superior colliculus, coupled with advances in experimental and statistical techniques including sophisticated behavioral procedures and multiple neuron recording and analysis, point toward a role for the basal ganglia-superior colliculus pathway in cognitive events intervening between vision and action, such as memory, target selection and saccade choice and valuation.

This review focuses on saccade research with adult psychiatric patients. It begins with an introduction of the various types of saccades and the tasks used to evoke them. The functional significance of the different types of eye movements is briefly discussed. Research findings regarding the saccadic performance of different adult psychiatric patient populations are discussed in detail, with particular emphasis on findings regarding error rates, response latencies, and any specific task parameters that might affect those variables. Findings regarding the symptom, neurocognitive, and neural correlates of saccadic performance and the functional significance of patients' saccadic deficits are also discussed. We also discuss the saccadic deficits displayed by various patient groups in terms of circuitry (e.g. cortical/basal ganglia circuits) that may be implicated in the underlying pathophysiology of several of these disorders. Future directions for research in this growing area are offered.

Spinal cord injury (SCI) is a debilitating clinical condition, characterized by a complex of neurological dysfunctions. Neural stem cells from the subventricular zone of the forebrain have been considered a potential tool for cell replacement therapies. We recently isolated a subclass of neural progenitors from the cadaver of mouse donors. These cells, named postmortem neural precursor cells (PM-NPCs), express both erythropoietin (EPO) and its receptor. Their EPO-dependent differentiation abilities produce a significantly higher percentage of neurons than regular NSCs. The cholinergic yield is also higher. The aim of the present study was to evaluate the potential repair properties of PM-NPCs in a mouse model of traumatic SCI. Labeled PM-NPCs were administered intravenously; then the functional recovery and the fate of transplanted cells were studied. Animals transplanted with PM-NPCs showed a remarkable improved recovery of hindlimb function that was evaluated up to 90 days after lesion. This was accompanied by reduced myelin loss, counteraction of the invasion of the lesion site by the inflammatory cells, and an attenuation of secondary degeneration. PM-NPCs migrate mostly at the injury site, where they survive at a significantly higher extent than classical NSCs. These cells accumulate at the edges of the lesion, where a reach neuropile is formed by MAP2- and β-tubulin III-positive transplanted cells that are also mostly labeled by anti-ChAT antibodies.

Background Non-human primates are an invaluable part of biomedical research. Strict regulations insure animals have a maximum likelihood of well-being and optimum health during the course of experimental procedures. Objective assessment of well-being is a critical component of these assurances. Methods Here we describe an objective and quantitative system we used to identify two well-being concerns in laboratory rhesus monkeys (Macaca mulatta). We provide a series of indicators for use by laboratory personnel to promote laboratory primate well-being. The indicators measure (1) potentially life threatening clinical concerns, (2) developing clinical issues, (3) atypical behaviors, and (4) laboratory performance. We include specific criteria to facilitate veterinary intervention. Results The assessment, applied to two case studies reported here, enabled swift veterinary intervention returning the animals to a healthy state. Conclusions The measures described here provide a battery of observable and objective measures across multiple dimensions that can further ensure both excellent science and veterinary care.

Neuroscientists from across the country gathered at the University of Wisconsin, Madison in September to honor Ray Guillery and his seminal work on the thalamus. The meeting focused on three timely research topics, each of which inspired new thinking about thalamic function. Presentations on the organization and dynamic nature of thalamocortical pathways, the role of the thalamus in communication between cortical areas, and the relationship between sensory and motor pathways of the brain, including cognitive aspects of thalamocortical processing, made for lively discussions. The meeting revealed that communication between thalamus and cortex is so rich that we should no longer consider the operations of either structure separately from the other. Proceedings of the meeting will be published in Progress in Brain Research in 2005. In this report, we provide a general overview of the main themes of the meeting.

Gaze-evoked blinks are contractions of the orbicularis oculi (OO)—the lid closing muscle—occurring during rapid movements of the head and eyes and result from a common drive to the gaze and blink motor systems. However, blinks occurring during shifts of gaze are often suppressed when the gaze shift is made to an important visual stimulus, suggesting that the visual system can modulate the occurrence of these blinks. In head-stabilized, human subjects, we tested the hypothesis that the presence of a visual stimulus was sufficient, but not necessary, to modulate OO EMG (OOemg) activity during saccadic eye movements. Rapid, reorienting movements of the eyes (saccades) were made to visual targets that remained illuminated (visually guided trials) or were briefly flashed (memory-guided trials) at different amplitudes along the horizontal meridian. We measured OOemg activity and found that the magnitude and probability of OOemg activity occurrence was reduced when a saccade was made to the memory of the spatial location as well as to the actual visual stimulus. The reduced OOemg activity occurred only when the location of the target was previously cued. OOemg activity occurred reliably with spontaneous saccades that were made to locations with no explicit visual stimulus, generally, back to the fixation location. Thus the modulation of gaze-evoked OOemg activity does not depend on the presence of visual information per se, but rather, results from an extraretinal signal.

Spinal cord injury is a devastating clinical condition, characterized by a complex of neurological dysfunctions. Animal models of spinal cord injury can be used both to investigate the biological responses to injury and to test potential therapies. Contusion or compression injury delivered to the surgically exposed spinal cord are the most widely used models of the pathology. In this report the experimental contusion is performed by using the Infinite Horizon (IH) Impactor device, which allows the creation of a reproducible injury animal model through definition of specific injury parameters. Stem cell transplantation is commonly considered a potentially useful strategy for curing this debilitating condition. Numerous studies have evaluated the effects of transplanting a variety of stem cells. Here we demonstrate an adapted method for spinal cord injury followed by tail vein injection of cells in CD1 mice. In short, we provide procedures for: i) cell labeling with a vital tracer, ii) pre-operative care of mice, iii) execution of a contusive spinal cord injury, and iv) intravenous administration of post mortem neural precursors. This contusion model can be utilized to evaluate the efficacy and safety of stem cell transplantation in a regenerative medicine approach.

Neural circuits that translate sensory information into motor commands are organized in a feedforward manner converting sensory information into motor output. The superior colliculus (SC) follows this pattern as it plays a role in converting visual information from the retina and visual cortex into motor commands for rapid eye movements (saccades). Feedback from movement to sensory regions is hypothesized to play critical roles in attention, visual image stability, and saccadic suppression, but in contrast to feedforward pathways, motor feedback to sensory regions has received much less attention. The present study used voltage imaging and patch-clamp recording in slices of rat SC to test the hypothesis of an excitatory synaptic pathway from the motor layers of the SC back to the sensory superficial layers. Voltage imaging revealed an extensive depolarization of the superficial layers evoked by electrical stimulation of the motor layers. A pharmacologically isolated excitatory synaptic potential in the superficial layers depended on stimulus strength in the motor layers in a manner consistent with orthodromic excitation. Patch-clamp recording from neurons in the sensory layers revealed excitatory synaptic potentials in response to glutamate application in the motor layers. The location, size, and morphology of responsive neurons indicated they were likely to be narrow-field vertical cells. This excitatory projection from motor to sensory layers adds an important element to the circuitry of the SC and reveals a novel feedback pathway that could play a role in enhancing sensory responses to attended targets as well as visual image stabilization.

Hyperexcitable reflex blinks are a cardinal sign of Parkinson’s disease. The first step in the circuit linking the basal ganglia and brainstem reflex blink circuits is the inhibitory nigrostriatal pathway (Basso et al., 1996). The current study reports the circuits linking the superior colliculus (SC) to trigeminal reflex blink circuits. Microstimulation of the deep layers of the SC suppresses subsequent reflex blinks at a latency of 5.4 msec. This microstimulation does not activate periaqueductal gray antinociceptive circuits. The brainstem structure linking SC to reflex blink circuits must suppress reflex blinks at a shorter latency than the SC and produce the same effect on reflex blink circuits as SC stimulation, and removal of the structure must block SC modulation of reflex blinks. Only the nucleus raphe magnus (NRM) meets these requirements. NRM microstimulation suppresses reflex blinks with a latency of 4.4 msec. Like SC stimulation, NRM microstimulation reduces the responsiveness of the spinal trigeminal nucleus. Finally, blocking the receptors for the NRM transmitter serotonin eliminates SC modulation of reflex blinks, and muscimol inactivation of the NRM transiently prevents SC modulation of reflex blinks. Thus, the circuit through which the basal ganglia modulates reflex blinking is (1) the substantia nigra pars reticulata inhibits SC neurons, (2) the SC excites tonically active NRM neurons, and (3) NRM neurons inhibit spinal trigeminal neurons involved in reflex blink circuits.

How the brain selects goals for movements remains unknown. The system designed to move the eyes rapidly, the saccadic system, may play a role. Here we ask how sensory signals within a saccade area are influenced by selecting and preparing a saccade. Trained monkeys made or withheld saccades, based on a color cue, to targets varying in luminance contrast. We measured the initial visual activity of superior colliculus (SC) neurons in response to the appearance of these targets. We determined neuronal contrast responses in three task conditions: when two luminance gratings appeared one in the response field (RF) and one in the mirror-opposite location and a cue to select the stimulus in the RF occurred; when the gratings appeared and a cue to select the stimulus out of the RF occurred; and third, when the gratings appeared but monkeys remained fixating on the central spot. SC neurons had increases in visual responses when contrast increased. Receiver operating characteristic analysis revealed an increased ability of neurons to detect the grating on trials with higher contrast targets and also on trials with a cue to make a saccade compared with trials with a cue to remain fixating. Using two measures of neuronal sensitivity, those SC neurons considered part of the motor circuitry increased their sensitivity to contrast with a cue to make a saccade. The results indicate that movement commands influence sensory responses in SC in much the same way that commands to shift attention influence sensory responses in extrastriate cortex.

The technique of electrical stimulation of brain tissue-known clinically as deep brain stimulation (DBS)-is at the fore of treatment of human neurological disease. Here we provide a general overview highlighting the anatomy and circuitry of the basal ganglia (BG). We introduce common disease states associated with BG dysfunction and current hypotheses of BG function. Throughout this introductory review we direct the reader to other reviews in this special issue of Neuroscience and Biobehavioral Reviews highlighting the interaction between basic science and clinical investigation to more fully understand the BG in both health and disease.

The authors describe the rationale and methodology for the first prospective, multicenter, randomized clinical trial (RCT) of a task-oriented walking intervention for subjects during early rehabilitation for an acute traumatic spinal cord injury (SCI). The experimental strategy, body weight-supported treadmill training (BWSTT), allows physical therapists to systematically train patients to walk on a treadmill at increasing speeds typical of community ambulation with increasing weight bearing. The therapists provide verbal and tactile cues to facilitate the kinematic, kinetic, and temporal features of walking. Subjects were randomly assigned to a conventional therapy program for mobility versus the same intensity and duration of a combination of BWSTT and over-ground locomotor retraining. Subjects had an incomplete SCI (American Spinal Injury Association grades B, C, and D) from C-4 to T-10 (upper motoneuron group) or from T-11 to L-3 (lower motoneuron group). Within 8 weeks of a SCI, 146 subjects were entered for 12 weeks of intervention. The 2 single-blinded primary outcome measures are the level of independence for ambulation and, for those who are able to walk, the maximal speed for walking 50 feet, tested 6 and 12 months after randomization. The trial's methodology offers a model for the feasibility of translating neuroscientific experiments into a RCT to develop evidence-based rehabilitation practices.

633 Background: Ras genes are markers of resistance to anti-EGFR therapies. Emerging evidences suggest that each mutation, independently from its predictive role of response/resistance to specific treatments, may be expression of different diseases with different biologic behaviours. We collected data of mCRC patients harbouring K-Ras codon 13 mutation to evaluate response to therapy, PFS and OS. Methods: We retrospectively collected data of advanced colorectal cancer patients harbouring K-Ras codon 13 mutation treated at our Institution between 2004 and 2014. Results: A total of n.33 K-Ras codon 13 mutated patients were analysed. N.24 patients (72,7%) had synchronous metastatic disease. None of the patients received anti-EGFR treatment, while n.25 patients received anti-VEGF agent bevacizumab in association to chemotherapy with fluoropirimidines plus oxaliplatin and/or irinotecan (n.21 as frontline therapy, n.4 in second line). ORR was 51,5% (17/33) on first-line therapy, 22,2% (6/27) on second-line therapy and 16,6% (2/12) on third-line therapy. Median PFS was 14,1 months after first-line therapy, 9,3 months after second-line therapy, 6,4 months after third-line therapy. Median OS was 35,5 months (events: 19/33). N.14 patients received metastases surgery with radical intent. OS in this population has not been reached yet at a median follow-up of 38 months, even though all patients had a relapse. OS among patients undergone to systemic only strategy was 31 months. Conclusions: At our knowledge, this is the first report suggesting a favourable prognosis for K-ras codon 13 mutated patients, with a median overall survival even superior to pan-RAS wild-type patients. Indeed, the high percentage of advanced patients at diagnosis (72.7%), the high responsiveness to chemotherapy even in third line, the high percentage of patients converted to surgery (42.4%) in an unselected population, together with the high risk or relapse after surgery, suggest K-ras codon 13 mutated disease is probably a biologically aggressive disease. Nevertheless our data prompt that these patients may benefit aggressive strategies of treatment and multidisciplinary evaluation.

Complex visual scenes require that a target for an impending saccadic eye movement be selected from a number of possible targets. We investigated whether changing the number of stimuli from which a target would be identified altered the activity of substantia nigra pars reticulata (SNr) neurons of the basal ganglia (BG) and how such changes might contribute to changes we observed previously in the superior colliculus (SC). One, two, four, or eight visual stimuli appeared on random trials while monkeys fixated a centrally located spot. After a delay, one of the stimuli in the array changed luminance, indicating that it was the saccade target. We found that SNr neurons that had a pause in tonic activity after target onset and when the saccade was made to the target showed a modulation of activity during the multitarget task. Because the number of stimuli in the array increased from one to eight, the initial pause after the onset of the visual stimulus decreased. Activity during the preselection delay was reduced but was independent of the number of possible targets present. When one of the stimuli was identified as the saccade target, but before the saccade was made, we found a sharp decline in activity. This decline was related to the monkey's selecting the target rather than the luminance change identifying the target, because on error trials, when the luminance changed but a saccade was not made to the target, the activity did not decline. The decline for the preferred target location was also accompanied by a lesser decline for adjacent locations. Our findings indicate that SNr activity changes with target selection as it does with saccade initiation and that the SNr could make substantial, direct contributions to the SC at both times. The pause in SNr activity with target selection is consistent with the hypothesis that BG provide a disinhibition for the selection of desired movements.

Hyperexcitable reflex blinks are a cardinal sign of Parkinson’s disease. We investigated the neural circuit through which a loss of dopamine in the substantia nigra pars compacta (SNc) leads to increased reflex blink excitability. Through its inhibitory inputs to the thalamus, the basal ganglia could modulate the brainstem reflex blink circuits via descending cortical projections. Alternatively, with its inhibitory input to the superior colliculus, the basal ganglia could regulate brainstem reflex blink circuits via tecto-reticular projections. Our study demonstrated that the basal ganglia utilizes its GABAergic input to the superior colliculus to modulate reflex blinks. In rats with previous unilateral 6-hydroxydopamine (6-OHDA) lesions of the dopamine neurons of the SNc, we found that microinjections of bicuculline, a GABA antagonist, into the superior colliculus of both alert and anesthetized ratseliminatedthe reflex blink hyperexcitability associated with dopamine depletion. In normal, alert rats, decreasing the basal ganglia output to the superior colliculus by injecting muscimol, a GABA agonist, into the substantia nigra pars reticulata (SNr) markedlyreducedblink amplitude. Finally, brief trains of microstimulation to the superior colliculusreducedblink amplitude. Histological analysis revealed that effective muscimol microinjection and microstimulation sites in the superior colliculus overlapped the nigro-tectal projection from the basal ganglia. These data support models of Parkinsonian symtomatology that rely on changes in the inhibitory drive from basal ganglia output structures. Moreover, they support a model of Parkinsonian reflex blink hyperexcitability in which the SNr–SC target projection is critical.

489 Background: Oxaliplatin is widely used in metastatic colorectal cancer, but currently there are not valid predictors of response to this drug. In our recent retrospective clinical study we have shown a greater efficacy of Oxaliplatin in patients with metastatic colorectal cancer with mutated (mt) K-RAS. We hypothesized that the mutational status of K-RAS could influence the expression of ERCC1, one of the main mechanisms of Oxaliplatin resistance. Methods: We used four cell lines of colorectal cancer: two K-RAS wild type (wt) (HCT-8 and HT-29) and two K-RAS mt (SW620 and SW480). We evaluated the sensitivity of these cell lines to Oxaliplatin by MTT-test and the ERCC1 levels before and after 24 h exposure to Oxaliplatin by Real-Time PCR. We silenced K-RAS in a K-RAS mt cell line to evaluate the impact on Oxaliplatin sensitivity and ERCC1 levels. We also silenced ERCC1 in order to confirm the importance of this protein as a Oxaliplatin resistance factor. Results: The K-RAS mt cell lines were more sensitive to Oxaliplatin (OR 2.68; IC 95% 1.511-4.757 p Conclusions: The K-RAS mutated cell lines were more sensitive to Oxaliplatin. This feature seems to be secondary to the inability of these cells to induce ERCC1 after exposure to Oxaliplatin. K-RAS can thus be a predictor of response to Oxaliplatin in colorectal cancer representing a surrogate for ability to induce ERCC1.

500 Background: In the present study we have evaluated the possibility that KRAS mutational status might be predictive of the efficacy of oxaliplatin-based chemotherapy. In addition, we explored the possible role of excision repair cross complementing group-1 (ERCC-1) that is envolved in repair of oxaliplatin (OXA) produced DNA-adducts. Methods: We performed a retrospective analysis of 90 patients with metastatic colorectal cancer, who received FOLFOX-6 schedule and FOLFIRI schedule ± Bevacizumab, in first or second line therapy. In sixty out of 90 patients the expression of ERCC-1 was also determined by fluorescence-based real-time detection method. Results: Among 90 patients, 42 (47%) wild-type (wt) and 48 (53%) mutated (mt) KRAS tumors were found. Twenty-two out of 42 wt KRAS patients received FOLFOX-6 as first-line therapy and the other 20 patients as second-line treatment; in the mt KRAS population, 27 and 21 patients received FOLFOX-6 as front-line or second-line, respectively. One complete response (CR) and 10 partial responses (PR) were observed in the wt KRAS group (RR 26%), whereas 2 CR and 25 PR were obtained in the mt KRAS group (56%); the difference is statistically significant in the total sample (p=0.003) and when only patients receiving FOLFOX-6 in first-line are considered (p=0006). PFS was longer in mt than in wt KRAS patients in the entire group of patients (10 vs 8 months, respectively; p=0.001) and in those treated in front-line (10 vs 8 months, respectively; p=0.003). ERCC-1 was over-expressed in 30 out of 60 patients, but the efficacy of FOLFOX-6 was not different in patient showing high ERCC-1 levels in comparison to those with low level of the gene. In ERCC-1 over-expressing patients, however, RR and PFS were higher in mt than in wt patients (40% vs 13% and 10 vs 8 months, respectively); a similar, not significant, trend was also observed in patients not over-expressing ERCC-1. Conclusions: Our data, if confirmed in larger series and in a prospective setting, suggest that activating mutation of KRAS oncogene could be a predictive biomarker of response to oxaliplatin. Basal tumor expression of ERCC-1 doesn’t explain the high efficacy of FOLFOX-6 in mt KRAS patients.

Many vertebrates generate blinks as a component of saccadic gaze shifts. We investigated the nature of this linkage between saccades and blinking in normal humans. Activation of the orbicularis oculi, the lid closing muscle, EMG occurred with 97% of saccadic gaze shifts larger than 33 degrees. The blinks typically began simultaneously with the initiation of head and/or eye movement. To minimize the possibility that the blinks accompanying saccadic gaze shifts were reflex blinks evoked by the wind rushing across the cornea and eye-lashes as the head and eyes turned, the subjects made saccadic head turns with their eyes closed. In this condition, orbicularis oculi EMG activity occurred with all head turns greater than 17 degrees in amplitude and the EMG activity began an average of 39.3 ms before the start of the head movement. Thus, one component of the command for large saccadic gaze shifts appears to be a blink. We call these blinks gaze-evoked blinks. The linkage between saccadic gaze shifts and blinking is reciprocal. Evoking a reflex blink prior to initiating a voluntary saccadic gaze shift dramatically reduces the latency of the initiation of the head movement.

e11509 Background: The addition of BEV to chemotherapy in the first-line treatment of HER2-negative MBC has been evaluated in several trials, resulting in an improvement in progression-free surviva...

Poster: "ECR 2011 / C-1782 / Balloon-occluded percutaneous radio-frequency thermal ablation (RFA) plus transcatheter arterial chemoembolization (TACE): a new combined single-step therapy for treatment of unresectable hepatocellular carcinoma" by: "R. Iezzi, G. L. Rapaccini, A. M. De Gaetano, M. Pompili, A. Gasbarrini, L. Bonomo; Rome/IT"

The blink reflex abnormalities present in the 6 hydroxydopamine (6-OHDA) lesioned rat model of parkinsonism mimicked those of the human with Parkinson's disease. In alert rats, we monitored the long and short latency components of the orbicularis oculi electromyographic (OOemg) response evoked by electrical stimulation of the supraorbital branch of the trigeminal nerve (SO). Two paradigms, habituation and double pulse, provided a measure of blink reflex excitability. In normal rats, repeated stimulation of the SO produced habituation of the R2 component of the blink. In the double pulse paradigm, presentation of two identical SO stimuli resulted in a reduced or suppressed OOemg response to the second stimulus relative to the first. In rats with complete, unilateral lesions of midbrain dopamine neurons, repeated SO stimulation produced facilitation rather than habituation of the R2 component of the blink reflex. This facilitation occurred only with the eyelid contralateral to the lesion. In the double pulse paradigm, the lesioned rats showed increased excitability rather than suppression. This effect occurred bilaterally, although the increased excitability was strongest contralateral to the lesion. Rats with partial lesions of midbrain dopamine neurons exhibited qualitatively similar, but less pronounced blink reflex abnormalities. The R1 component of the blink reflex was unaffected by either the complete or partial lesions. Thus, modification of the blink reflex by 6-OHDA lesions provides a reproducible parkinsonian-like symptom which is amenable to investigations of increases in reflex excitability.

In humans and rats we found that nicotine transiently modifies the blink reflex. For blinks elicited by stimulation of the supraorbital branch of the trigeminal nerve, nicotine decreased the magnitude of the orbicularis oculi electromyogram (OOemg) and increased the latency of only the long-latency (R2) component. For blinks elicited by electrical stimulation of the cornea, nicotine decreased the magnitude and increased the latency of the single component of OOemg response. Since nicotine modified only one component of the supraorbitally elicited blink reflex, nicotine must act primarily on the central nervous system rather than at the muscle. The effects of nicotine could be caused by direct action on lower brainstem interneurons or indirectly by modulating descending systems impinging on blink interneurons. Since precollicular decerebration eliminated nicotine's effects on the blink reflex, nicotine must act through descending systems. Three lines of evidence suggest that nicotine affects the blink reflex through the basal ganglia by causing dopamine release in the striatum. First, stimulation of the substantia nigra mimicked the effects of nicotine on the blink reflex. Second, haloperidol, a dopamine (D2) receptor antagonist, blocked the effect of nicotine on the blink reflex. Third, apomorphine, a D2 receptor agonist, mimicked the effects of nicotine on the blink reflex.

e14557 Background: In 2007, sorafenib (SOR) was shown effective in improving overall survival (OS) when compared to best supportive care in patients with hepatocellular carcinoma (HCC) and a good liver function (Child A). Sunitinib is another multi-kinase inhibitor that is active against VEGF-R, PDGF-R and c-KIT. We designed a phase II study, according with a two-step Simon's model, to assess safety and efficacy of sunitinib in HCC patients. Methods: Eligibility criteria were: unresectable or metastatic HCC; no prior chemotherapy. PS (ECOG) 0-1; measurable disease according to RECIST criteria. Child C patients were excluded. Schedule: 50 mg each day, four weeks on, two weeks off. CT scan: every two cycles. PET-TC scan: at baseline and after the first cycle. Primary end-point was response rate according to RECIST criteria. Results: Thirty-three patients enrolled. ChildA/ChildB = 21/12 (64%/36%). Seventy-five cycles were administered. Grade 3 adverse effects included fatigue (26.6% of cycles), piastrinopeni...

e14600 Background: Sunitinib, an oral multitargeted tyrosine kinase inhibitor, showed encouraging results on time to tumor progression against advanced hepatocellular carcinoma (HCC) (Lancet Oncol ...

1580 Backgrond: Treatment of unresectable high grade gliomas still remains a controversal item. After surgery and radiotherapy, chemotherapy is the only chance for these patients (pts) even though ...

4188 Background: Chemotherapy is the only treatment option for advanced gastric cancer (AGC) patients (pts). First line regimens are able to provide a slight but significant increase of survival ra...