Prime Trials Research Articles

Is Language Production Planning Emergent From Action Planning? A Preliminary Investigation.

The nature of syntactic planning for language production may reflect language-specific processes, but an alternative is that syntactic planning is an example of more domain-general action planning processes. If so, language and non-linguistic action planning should have identifiable commonalities, consistent with an underlying shared system. Action and language research have had little contact, however, and such comparisons are therefore lacking. Here, we address this gap by taking advantage of a striking similarity between two phenomena in language and action production. One is known as syntactic priming—the tendency to re-use a recently produced sentence structure—and the second is hysteresis—the tendency to re-use a previously executed abstract action plan, such as a limb movement. We examined syntactic priming/hysteresis in parallel language and action tasks intermixed in a single experimental session. Our goals were to establish the feasibility of investigating language and action planning within the same participants and to inform debates on the language-specific vs. domain-general nature of planning systems. In both action and language tasks, target trials afforded two alternative orders of subcomponents in the participant’s response: in the language task, a picture could be described with two different word orders, and in the action task, locations on a touch screen could be touched in two different orders. Prime trials preceding the target trial promoted one of two plans in the respective domain. Manipulations yielded higher rates of primed behavior in both tasks. In an exploratory cross-domain analysis, there was some evidence for stronger priming effects in some combinations of action and language priming conditions than others. These results establish a method for investigating the degree to which language planning is part of a domain-general action planning system.

Phase II trial of guadecitabine priming and pembrolizumab in platinum resistant recurrent ovarian cancer.

6025 Background: Platinum resistant ovarian cancer (PROC) remains a disease of high need. Immune checkpoint inhibitors (ICI) have modest activity. We hypothesized that priming with a hypomethylating agent (HMA) guadecitabine (G) will improve the anti-tumor activity of ICI in PROC by enhancing tumor cell recognition by CD8+ T cells. Methods: This open-label phase II study used a Simon’s two-stage design. Eligible patients (pts) had recurrent PROC; ECOG PS of 0-1; normal end organ function; and measurable disease. Up to 5 prior cytotoxic regimens were allowed. Treatment consisted of G 30mg/m2 sq D1-4 and pembrolizumab (P) 200mg iv D5. Each cycle was 21 days. The primary endpoint was response rate (RR). Secondary endpoints were progression-free survival (PFS), clinical benefit rate (CBR), and toxicity assessment. Translational endpoints were LINE1 methylation in PBMCs, global tumor methylation, and immune endpoints. Tumor biopsies were obtained at baseline and after 2 cycles. If 2 patients experienced clinical benefit in stage I [n = 16], enrollment proceeded to stage II. The null hypothesis was rejected for ≥ 6 responses in 35 evaluable patients. Results: 48 pts were enrolled, 43 were treated, and 33 were evaluable for response. Histology was serous (35), endometrioid (2), clear cell (3) and other (3). Median age was 63 (range 40-88) and median number of prior regimens was 4 [range 1-8]. Two PRs were recorded in the first stage, allowing second stage of enrollment. Overall, there were 2 PRs (RR = 6.6%) and 16 pts had stable disease (SD) [48%]. The clinical benefit rate (PR + SD > 3 months) was 27%. One patient continued treatment for > 2 yrs. Grade 3-4 related toxicities were neutropenia [20], lymphopenia, (9), anemia (2), neutropenic fever (1), rash (1), and others (8). There were 13 grade 3-4 SAEs and 4 grade 5 SAEs, assessed as being unrelated to treatment. LINE1 was hypomethylated in PBMCs D5 vs. D1 (n = 21, p = 0.001). Epic arrays measured global tumor methylation, with 39579 CpG sites (0.05%) being differentially methylated (C2D5 vs. C1D1, n = 11, paired t-test; p < 0.01). Main pathways affected included endosomal transport, K+ transport, cathecolamine secretion, etc. PDL1 staining in archival tissue showed tumor staining > 0 in 16 of 35 and tumor/stroma interface staining > 0 in 20 of 35 specimens. Antigen-specific cytotoxic T cell activity was increased in CD8+ cells from ascites (C2D5 vs. C1D1). Conclusions: G+P has modest anti-tumor activity in patients with PROC, but some patients experienced prolonged disease stabilization. Biomarkers of response are being investigated. Clinical trial information: NCT02901899.

Learning from amyloid trials in Alzheimer's disease. A virtual patient analysis using a quantitative systems pharmacology approach.

BackgroundMany trials of amyloid‐modulating agents fail to improve cognitive outcome in Alzheimer's disease despite substantial reduction of amyloid β levels.MethodsWe applied a mechanism‐based Quantitative Systems Pharmacology model exploring the pharmacodynamic interactions of apolipoprotein E (APOE), Catechol ‐O ‐methyl Transferase (COMTVal158Met), and 5‐HT transporter (5‐HTTLPR) rs25531 genotypes and aducanumab.ResultsThe model predicts large clinical variability. Anticipated placebo differences on Alzheimer's Disease Assessment Scale (ADAS)‐COG in the aducanumab ENGAGE and EMERGE ranged from 0.77 worsening to 1.56 points improvement, depending on the genotype‐comedication combination. 5‐HTTLPR L/L subjects are found to be the most resilient. Virtual patient simulations suggest improvements over placebo between 4% and 20% at the 10 mg/kg dose, depending on the imbalance of the 5‐HTTLPR genotype and exposure. In the Phase II PRIME trial, maximal anticipated placebo difference at 10 mg/kg ranges from 0.3 worsening to 5.3 points improvement.DiscussionThese virtual patient simulations, once validated against clinical data, could lead to better informed future clinical trial designs.

Study protocol of a randomised controlled trial of prostate radiotherapy in high-risk and node-positive disease comparing moderate and extreme hypofractionation (PRIME TRIAL)

IntroductionThere has been an interest in studying the efficacy of extreme hypofractionation in low and intermediate risk prostate cancer utilising the low alpha/beta ratio of prostate. Its role in high-risk...

Introspection about backward crosstalk in dual-task performance

The present study investigated participants’ ability to introspect about the effect of between-task crosstalk in dual tasks. In two experiments, participants performed a compatibility-based backward crosstalk dual task, and additionally provided estimates of their RTs (introspective reaction times, IRTs) after each trial (Experiment 1) or after each pair of prime and test trials (Experiment 2). In both experiments, the objective performance showed the typical backward crosstalk effect and its sequential modulation depending on compatibility in the previous trial. Very similar patterns were observed in IRTs, despite the typical unawareness of the PRP effect. In sum, these results demonstrate the reliability of between-task crosstalk in dual tasks and that people’s introspection about the temporal processing demands in this complex dual-task situation is intriguingly accurate and severely limited at the same time.

Freely-selected and forced-choice responses bind with relevant object-occupied locations in visuospatial tasks.

Past work has shown that cued manual responses in visuo-identity tasks bind to irrelevant stimulus features, present at the time these responses were executed (prime trial). These response bindings manifested their existence via impacts on later related processing (probe trial). Here, we extended this prior research by showing that response binding is likely a pervasive processing characteristic. We saw that uncertain prime-trial responses (i.e., free-choice, forced-choice) did bind to the relevant "location" feature of the prime stimulus in a visuospatial task (i.e., R-L binding). Overall, R-L binding evidence was better for within-hand than for between-hand probe-trial finger competitions and better for probe trial response selection preferences than for their reaction time (RT) data. R-L binding evidence was entirely absent, however, for forced-choice probe trials. Evidence that the prime response binds to irrelevant prime display features (i.e., prime stimulus identity [R-I binding]) was virtually absent. Other results indicated that R-I likely exists, but that its probe-trial manifestation is prevented by the involvement of R-L binding. Response binding impacts on later processing should be considered when interpreting RT data. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The PRIME Trial: PARP Inhibition in IDH Mutant Effectiveness Trial. a Phase II Study of Olaparib in Isocitrate Dehydrogenase (IDH) Mutant Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome

Background: Recurring mutations have been identified in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) which translate to therapeutic targets. Isocitrate dehydrogenase-1 and -2 (IDH1/2) mutations occur in ~20% of AML, and up to 12% of patients with MDS. Three conserved mutational hotspots in the IDH enzymes alter their function and lead to the production of (R)-2-hydroxyglutarate (2HG), an oncometabolite with numerous downstream effects, including impaired DNA damage repair. Specifically, homologous recombination (HR) is impaired by inhibiting the function of histone demethylases that are critical for HR and recruitment of the HR machinery to sites of DNA damage. In HR deficient tumors poly-ADP ribose polymerase (PARP) enzymes mediate a key salvage pathway. PARP inhibition in HR deficient tumors leads to synthetic lethality via simultaneous inhibition of HR and SSB mediated DNA repair. Our group previously demonstrated synthetic lethality with PARP inhibition in IDH mutant cells lines, and other IDH mutant models including primary patient-derived cell lines and genetically-matched tumor xenografts. Study Design and Methods: The PRIME trial (NCI10264) is a proof of concept, biomarker-driven, multi-institution, phase II open label clinical trial to assess the overall response of IDH1/2 mutant relapsed/refractory AML and MDS to PARP inhibitor monotherapy with olaparib. The clinical trial is executed by the Experimental Therapeutics Clinical Trials Network of the NCI. The Cancer Therapy Evaluation Program will provide olaparib. Eligibility criteria include documented IDH1 or IDH2 mutation in blood or bone marrow within 30 days of enrollment based on mutational testing by PCR or sequencing in a CLIA certified laboratory and willingness to undergo a bone marrow biopsy. Patients will be treated with olaparib 300 mg q12hrs each day of a 28-day cycle, using a tablet formulation, until disease progression, unacceptable toxicity, withdrawal of consent or death. Blood and bone marrow samples for 2-HG analysis will be collected prior to starting therapy and after 1 cycle (28 days), cycle 2, 3, 6, 9, 12 or when there is concern for disease progression (Figure 1). A Simon two-stage optimal design will be used to test the null (ORR=10%) versus the alternative hypothesis (ORR=40%) in each arm. In the first stage, 9 patients will be accrued in each arm. If one or fewer responses are observed in these 9 patients, that arm will be stopped early for futility. Otherwise, 11 additional patients will be accrued for a total of 18 in each arm. We reject the null hypothesis if at least 5 responses are observed in these 20 patients. In each arm, we have approximately 90% power to detect a 30% increase in ORR at a one-sided type I error rate of 0.05. Primary endpoint: Overall response rate (ORR) of 40%, i.e., a 30% ORR improvement (40% vs. historical control ORR = 10%) based on MDS International Working Group 2006 criteria and AML MDS International Working Group 2003 criteria after 6 cycles of treatment. Cumulative ORR will include complete remission, complete remission with incomplete blood count recovery, partial response, and bone marrow complete remission. Secondary endpoints: Progression-free survival (the interval between the time of initiation of olaparib to the time of documentation of olaparib failure or last follow-up) and overall survival (the interval between the time of initiation of olaparib to the time of death or last follow-up) for the trial. Exploratory studies: The PRIME trial will also test the utility of 2-HG and DNA damage markers such as γ-H2AX as potential biomarkers of response to olaparib. Using multiple viability assays on leukemia cell lines and bone marrow cultures we will assess synergistic therapeutic combinations to further improve outcomes in this patient population. To confirm efficacy in vivo without undue toxicity, promising combination therapies will be confirmed in cytokine-humanized immunodeficient "MISTRG" mice. We will also examine the impact of PARP inhibitors on the genomic, proteomic, metabolomic and immunologic landscape of IDH 1/2-mutant hematologic malignancies using DNA whole exome sequencing (WES), RNA-Seq, and liquid chromatography-mass spectrometry assessment of oncometabolites. Disclosures Bindra: Cybrexa: Consultancy, Equity Ownership. Prebet:pfizer: Honoraria; pfizer: Honoraria; pfizer: Honoraria; Boehringer Ingelheim: Research Funding; pfizer: Honoraria; Tetraphase: Consultancy; novartis: Honoraria; novartis: Honoraria; Genentech: Consultancy; Boehringer Ingelheim: Research Funding; novartis: Honoraria; Boehringer Ingelheim: Research Funding; Agios: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; pfizer: Honoraria; novartis: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; novartis: Honoraria. OffLabel Disclosure: We will be using PARP inhibitors as a novel therapy for patients with relapsed or refractory AML and high risk MDS based on preclinical data.

Event-related potentials in pragmatic priming

Priming of pragmatic enrichment has been found in behavioural studies. We extend this by examining the neural correlates of priming for two implicature categories, quantifiers and disjunctions. Participants engaged in a primed sentence-picture matching task where they were presented with a sentence (e.g., “some of the letters are Bs”) followed by a picture. In prime trials the pictures were either consistent with an enriched interpretation (some but not all) or a basic interpretation (some and possibly all) of the sentence. The pictures in target trials were always consistent with the enriched interpretation. Using ERPs, we found a priming effect on the picture reflected in a reduced positivity for quantifiers when the preceding trial had an enriched interpretation, and no effect for disjunction. The pragmatic priming effect can be dissociated from expectation-based processes. It suggests that abstract derivation processes are primed during pragmatic alignment.

Magnitude of Benefit of Combined Endovascular Thrombectomy and Intravenous Fibrinolysis in Large Vessel Occlusion Ischemic Stroke.

Background and Purpose- Quantifying the benefit magnitude of combined endovascular thrombectomy (EVT) and intravenous thrombolysis (IVT) versus nonreperfusion care in patients with acute ischemic stroke caused by large vessel occlusion would aid organization of regional stroke care systems. Methods- NINDS rt-PA Study (National Institute for Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator) and SWIFT PRIME trial (Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment) patients were matched for prognosis (based on age and National Institutes of Health Stroke Scale) and definite/likely anterior circulation large vessel occlusion (based on National Institutes of Health Stroke Scale total score and item pattern), using optimal inverse variance matching, to determine comparative outcomes with nonreperfusion care alone, IVT alone, and IVT+EVT. Results- Matching yielded 240 patients, including 80 each treated with nonreperfusion care, IVT alone, and IVT+EVT, with, respectively, mean age 67.1, 67.1, and 66.9 and presenting deficit severity (National Institutes of Health Stroke Scale) mean 15.8, 15.9, and 15.9. Outcomes at 3 months for IVT+EVT versus nonreperfusion care included freedom from disability (modified Rankin Scale score, 0-1) 48.1% versus 21.3%, P=0.0004; functional independence (modified Rankin Scale score, 0-2) 62.9% versus 32.6, P=0.0001; and reduced disability over all 7 modified Rankin Scale levels, common odds ratio 3.34, P<0.0001. Outcomes for IVT alone versus nonreperfusion care included: freedom from disability 30.0% versus 21.3%, P=0.28 and reduced disability over all 7 modified Rankin Scale levels, common odds ratio 1.14, P=0.65. Compared with nonreperfusion care, the number needed to treat with EVT+IVT for 1 more patient to have reduced disability was 1.8. Conclusions- Matched patient analysis across randomized trials provides evidence that the strategy of combined IVT and mechanical thrombectomy is a highly beneficial treatment strategy for acute ischemic stroke caused by large vessel occlusion patients. A reasonable effect magnitude estimate is that, among every 100 patients treated, combined IVT+EVT reperfusion therapy, compared with no reperfusion therapy, reduces long-term disability in 57, including conferring functional independence upon 30.

The impact of general anesthesia, baseline ASPECTS, time to treatment, and IV tPA on intracranial hemorrhage after neurothrombectomy: pooled analysis of the SWIFT PRIME, SWIFT, and STAR trials

BackgroundDespite the proven benefit of neurothrombectomy, intracranial hemorrhage (ICH) remains the most serious procedural complication. The aim of this analysis was to identify predictors of different hemorrhage subtypes and evaluate...

The parametric estimation procedure to predict long-term efficacy on survival from publication data of clinical trials for metastatic colorectal cancer (mCRC).

541 Background: In comparative clinical trials with time-to-event outcomes, the long-term treatment effect profile is clinically crucial. The conventional non-parametric measures, i.e., the median survival times and the t-year survival rates are informative but sometimes cannot be observed due to the limited study follow-up. For example, in the PEAK trial (Schwartzberg LS et al. J Clin Oncol 2014), the group contrast over 3 years could not be adequately confirmed due to the short follow-up. To predict the subsequent survival prognosis with the limited outcome data, one may estimate the survival curve using a parametric model. Here, we illustrate the parametric estimation procedure to predict long-term efficacy using the results of two randomized controlled trials for the patients with wild-type KRAS mCRC, i.e., PRIME (Douillard JY et al. J Clin Oncol 2010, Douillard JY et al. Ann Oncol 2014) and PEAK trials. Methods: We considered both the primary and updated results for the PRIME to assess the validity of the procedure, and then estimated the long-term efficacy in the two trials. We used the reconstructed overall survival (OS) data obtained by scanning the Kaplan-Meier curves in the literature. Fitting the data to the Weibull distribution, we estimated the parametric group contrast measures including the difference in the 3- and 5-years restricted mean survival times and mean survival times. Results: The extrapolated parametric OS curves from the primary PRIME results fitted well with the observed Kaplan-Meier curves for OS in the updated results. The parametric estimations demonstrated that, in the PRIME trial, panitumumab plus FOLFOX arm increased 2.0 (95% CI: 0.1-4.0), 4.0 (0.5-7.5), and 5.4 (0.3-10.5) months in survival on average over 3-, 5-years and the entire time, respectively, compared to FOLFOX arm. In PEAK trial, compared to bevacizumab plus FOLFOX arm, panitumumab plus FOLFOX arm increased 3.6 (0.7-6.5), 7.9 (2.1-13.7), and 12.8 (0.5-25.1) months in survival on average, respectively. Conclusions: The estimators for parametric survival curve would provide the informative summaries for long-term survival profile to the clinicians and patients.

Abstract WP80: Association of Clot Burden Score and Thrombectomy 6 to 24 Hours After Stroke: Analysis of the DAWN Trial

Introduction: Clot burden score (CBS) is developed to evaluate anterior circulation ischemic stroke thrombus extent. Lower CBS is associated with worse functional outcome in an analysis of MR CLEAN trial without modifying the effect of mechanical thrombectomy within 6 hours after symptoms onset. An analysis of SWIFT PRIME trial showed that stent-retriever thrombectomy successfully recanalize regardless of CBS. However, thrombus that remains stagnant for longer period may be further compressed by the water-hammer effect of the systolic blood pressure, resulting in removal difficulty. We aim to explore relation of CBS with mechanical thrombectomy (MT) in the extended 6-24 hours of the DAWN trial. Method: A blinded assessor evaluated CBS in all patients receiving CTA brain in the multicenter randomized DAWN trial for MT in acute large vessel occlusion last known well 6-24 hours (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake up and Late Presenting Strokes Undergoing Neurointervention). The cohort was divided into low CBS (0-4) and high CBS (5-10) groups. We used ordinal logistic regression for analysis of association with good outcome (mRS≤2), adjusted for significant baseline variables. Results: 143 patients were included. Low CBS group consisted of 50 patients (29 received MT and 21 received medical management). High CBS group consisted of 93 patients (44 received MT and 49 received medical management). Baseline demographics were similar between groups. Low CBS group showed no difference in the odd of good outcome, adjusted OR 0.58 (0.3-1.14). Analysis of MT cases, Low CBS group showed a strong trend to higher procedure time (81.5±55.2 versus 56.4±35.3 min, p=0.07). There was no association of Low CBS and odds of good outcome (OR 0.9; 0.27-2.92), successful recanalization (OR 0.58; 0.18-1.89), and symptomatic intracranial hemorrhage (OR 1.67, 0.55-5.09). Conclusion: Despite literature reporting worse outcome of anterior circulation ischemic stroke with low CBS, acute large vessel occlusion stroke with last known well 6-24 hours and low CBS treated with thrombectomy was feasible and not associated with worsen outcome compared to high CBS. However, a strong trend to higher procedure time is observed.

What Is the Best Systemic Therapy for Left-sided RAS Wild-type Metastatic Colorectal Cancer?

There is a significant difference in embryological origin, gene expression, gene mutation profile, and microbiome between the right-sided and left-sided colon. It has been shown that the sidedness of primary colorectal cancer is a significant prognostic factor and predictive to the clinical benefit of anti-epidermal growth factor receptor (EGFR) antibody-containing chemotherapy in patients with metastatic CRC. Herein, current clinical recommendations for the treatment of patients with left-sided RAS wild-type mCRC are reviewed. Retrospective analyses of prior randomized trials (CRYSTAL, PRIME, FIRE-3, CALGB 80405, and PEAK trials) showed that primary tumor sidedness is predictive to anti-EGFR antibody therapy in the first-line treatment of patients with RAS wild-type mCRC, and patients with left-sided RAS wild-type mCRC had a significantly better survival benefit with anti-EGFR antibody plus chemotherapy when compared with anti-VEGF treatment plus chemotherapy. The primary tumor sidedness is a significant prognostic factor and predictive to anti-EGFR antibody-containing chemotherapy in patients with metastatic CRC. Based on the currently available data, chemotherapy plus anti-EGFR antibody is recommended for the first-line treatment of patients with left-sided RAS wild-type mCRC. Chemotherapy plus bevacizumab or anti-EGFR antibody is recommended for the second-line therapy of RAS wild-type mCRC regardless of sidedness. However, these recommendations are based on the limited data from the retrospective analyses of prior trials, warranting further prospective randomized trials.

Impact of Anesthetic Management on Safety and Outcomes Following Mechanical Thrombectomy for Ischemic Stroke in SWIFT PRIME Cohort.

Background and purpose: The optimal anesthetic management of acute ischemic stroke patients during mechanical thrombectomy (MT) remains controversial. In this post-hoc analysis, we investigated the impact of anesthesia type on clinical outcomes in patients included in SWIFT PRIME trial.Methods: Ninety-seven patients treated with MT were included. Patients treated in centers with general anesthesia (GA) policy (n = 32) were compared with those treated in centers with conscious sedation (CS) policy (n = 65). Primary outcomes studied included times to treatment initiation (TTI), rates of successful recanalization (TICI 2b/3), and functional independence (mRS 0–2 at 90 days). Secondary outcomes were adverse events, lowest systolic and diastolic blood pressures (LSBP and LDBP) during MT. Univariate analysis and multivariate regression logistic modeling were conducted.Results: The GA-policy and CS-policy groups presented comparable TTI (94 ± 36 min vs. 102 ± 48 min; p = 0.44), rates of TICI 2b/3 recanalization (22/32 [68.8%] vs. 51/65 [78.5%]; p = 0.32). CS-policy was associated to higher rate of functional independence than GA-policy, but the difference was not significant (43/65 [66.2%] vs. 16/32 [50.0%]; p = 0.18). GA-policy patients had a higher rate of postoperative pneumonia (11/32 [34.4%] vs. 8/65 [12.3%]; p = 0.02) and lower LSBP (110 [30,160] mmHg vs. 119 [77,170] mmHg; p = 0.03) and LDBP (55 (15,75) mmHg vs. 67 [40,121]; p < 0.001). When corrected for differences in baseline characteristics, GA-policy was associated with lower rate of functional independence (OR 0.32; p = 0.05). A 10-point increase in perprocedural LDBP was associated with an increased likelihood of favorable outcome (OR 1.51; p = 0.01).Conclusions: GA-policy for MT presented comparable TTI and rates of successful revascularization to CS-policy. However, GA-policy was associated with lower rates of functional independence and with higher incidence of perprocedural hypotension and postoperative pneumonia.Clinical Trial Registration: URL—http://www.clinicaltrials.gov. Unique identifier: NCT01657461

Memory-guided selective attention: Single experiences with conflict have long-lasting effects on cognitive control.

Adjustments in cognitive control, as measured by congruency sequence effects, are thought to be influenced by both external stimuli and internal goals. However, this dichotomy has often overshadowed the potential contribution of past experience stored in memory. Here, we examine the role of long-term episodic memory in guiding selective attention. Our aim was to demonstrate new evidence that selective attention can be modulated by long-term retrieval of stimulus-specific attentional control settings. All the experiments used a modified flanker task involving multiple unique stimuli. Critically, each stimulus was only presented twice during the experiment: first as a prime, and second as a probe. Experiments 1 and 2 varied the number of intervening trials between prime and probe and manipulated the amount of conflict using a secondary task. Experiment 3 ensured that specific colors assigned to prime stimuli were not repeated when presented as probes. Across both Experiments 1 and 2, we consistently found smaller congruency effects on probe trials when its associated prime trial was incongruent compared with congruent, demonstrating long-term congruency sequence effects. However, Experiment 3 showed no evidence for long-term effects. These findings suggest long-term preservation of selective attention processing at the episodic level, and implicate a role for memory in updating cognitive control. (PsycINFO Database Record

Relationships between tumour response and primary tumour location, and predictors of long-term survival, in patients with RAS wild-type metastatic colorectal cancer receiving first-line panitumumab therapy: retrospective analyses of the PRIME and PEAK clinical trials

BackgroundData from two trials of panitumumab in metastatic colorectal cancer (mCRC) were retrospectively analysed to investigate the effects of primary tumour location on early-tumour shrinkage (ETS) and depth of response (DpR), and identify factors predicting long-term survival.MethodsPatients with RAS wild-type mCRC from PRIME (NCT00364013) and PEAK (NCT00819780) were included. ETS was defined as a ≥30% reduction in the sum-of-the-longest-diameters of measurable target lesions at eight weeks. DpR was the maximum percentage change from baseline to nadir in patients with shrinkage. Univariate and multivariate logistic analyses of short- versus long-term survivor data were performed.ResultsA total of 435/559 (78%) patients had left-sided disease. Of these, a higher proportion of patients treated with panitumumab versus comparator achieved ETS (PRIME: 62% vs. 36%; PEAK: 58% vs. 41%); median DpR was also higher with panitumumab (PRIME: 59% vs. 49%; PEAK: 70% vs. 48%). In pooled analyses of the studies, more patients with right-sided disease achieved ETS if treated with panitumumab than comparator (39% vs. 29%). Panitumumab treatment consistently predicted long-term survival.ConclusionsFirst-line panitumumab was associated with improved ETS and DpR vs. comparator in patients with left-sided mCRC. ETS may identify a subgroup of patients with right-sided disease who might respond to panitumumab.

The nature of shape constancy mechanisms as revealed by shape priming.

Five shape priming experiments are reported in which the target was either a five- or six-sided line-drawn figure and participants made a speeded two-alternative forced-choice judgment about the target's number of sides. On priming trials, the target was preceded by a briefly presented smaller line figure (the prime) and performance on these trials was gauged relative to a no-prime condition. In the first two experiments, primes were rendered invisible by the presentation of a backwards visual noise mask, respectively for a short (∼40 ms) or long duration (∼93 ms). No reliable priming effects arose under masked conditions. When these experiments were repeated without the mask, participants were speeded when the prime and target were related by a rigid through-the-plane rotation but not when the prime was a nonrigid, stretched version of the target. The same pattern of priming effects arose when, in a final experiment, novel irregular shapes were used. Collectively, the data reveal the operation of shape constancy mechanisms that are particularly sensitive to shape rigidity. The findings suggest that the visual system attempts to secure a correspondence between the rapid and successive presentations of the prime and the target by matching shapes according to a rigidity constraint.

Automatic stimulus evaluation depends on goal relevance.

To examine whether automatic stimulus evaluation is dependent upon goal relevance, participants were presented with a mixture of (a) goal-induction trials to create a set of goal-relevant and goal-irrelevant stimuli, and (b) evaluative priming trials to capture the automatic evaluation of these stimuli as good or bad. In line with our predictions, a reliable evaluative priming effect was obtained only for stimuli that were relevant for the goal-induction task. Implications for the use of the evaluative priming paradigm as an assessment tool and the replicability of the evaluative priming effect in the absence of dimensional overlap between the prime set and the target set are discussed. (PsycINFO Database Record

Improvement of Oxygen-Uptake Kinetics and Cycling Performance With Combined Prior Exercise and Fast Start.

To investigate whether oxygen-uptake ([Formula: see text]) kinetics and simulated 4-km cycling performance are synergistically improved by prior "priming" exercise and an all-out starting strategy. Nine men completed 4 target work trials (114 ± 17kJ) to assess [Formula: see text] kinetics and cycling performance in a repeated-measures, crossover experimental design. Trials were initiated with either a 12-s all-out start or a self-selected start and preceded by prior severe-intensity (70%Δ) priming exercise or no priming exercise. The [Formula: see text] mean response time (MRT) was lower (indicative of faster [Formula: see text] kinetics) in the all-out primed condition (20 ± 6s) than in the all-out unprimed (23 ± 6s), self-paced-unprimed (42 ± 13s), and self-paced-primed (42 ± 11s) trials (P < .05), with the [Formula: see text] MRT also lower in the all-out unprimed than the self-paced unprimed and self-paced primed trials (P < .05). Trial-completion time was shorter (performance was enhanced) in the all-out primed trial (402 ± 14s) than in the all-out unprimed (408 ± 14s), self-paced unprimed (411 ± 16s), and self-paced primed (411 ± 19s) trials (P < .05), with no differences between the latter 3 trials. The findings from this study suggest that combining severe-intensity priming exercise with a short-duration all-out starting strategy can expedite the adjustment of [Formula: see text] and lower completion time during a cycling performance trial to a greater extent than either intervention administered independently. These results might have implications for optimizing performance in short-duration high-intensity competitive events such as a 4-km cycling time trial.

Abstract TMP5: Acute Ischemic Stroke due to Large Vessel Occlusions: Incremental Benefits of IV tPA Alone and Mechanical Thrombectomy Added to IV tPA

Background: Quantifying the magnitude of benefit of mechanical thrombectomy (MT) add to IV tPA (IVT) versus IV tPA alone vs neither in patients with acute ischemic stroke due to large vessel occlusion (LVO-AIS) is crucial to optimal organization of regional systems of stroke care. But single RCT analysis cannot quantify these effect magnitudes as no IV tPA trial enrolled explicitly-identified LVO patients, and no thrombectomy trial enrolled early IV tPA responders. Methods: We performed a matched patient network analysis of the two NINDS-tPA trials and the SWIFT PRIME trial. Using 1:1 optimal inverse variance matching, with NIHSS ± 1 and age ± 5, triplet matched were made between the NINDS placebo (neither MT or IVT), NINDS tPA (tPA only), and SWIFT PRIME (MT+IVT) treatment groups, ensuring comparable LVO-AIS patients, and 90 day mRS outcomes analyzed. Results: Among 258 triplet matched patients (86 in each treatment arm), baseline characteristics were well balanced for age (MT+IVT 66.6, IVT only 66.5, neither 66.7, p=1.00) and presenting deficit severity (NIHSS 16.3 vs 16.4 vs 16.2, p=0.98). Dramatic early benefits of IVT, leading to foregoing of MT, occurred in 10.1% of patients. The Figure shows final 90 day mRS distributions for the 3 AIS-LVO treatment strategies. Freedom from disability (mRS 0-1) was higher with MT+IVT than IVT alone and neither (47.7% vs 31.4% vs 19.8%), as was functional independence (mRS 0-2, 64.2% vs 37.2% 30.2%), and severe disability/death (mRS 5-6) was lower (11.0% vs 29.1% vs 31.4%). Number needed to treat for 1 improved outcome over the entire mRS range (shift analysis) was 4.9 for IVT alone vs neither and 2.0 for both MT+IVT vs neither. Conclusions: The strategy of IV thrombolysis plus direct mechanical thrombectomy unless immediate dramatic benefit occurs is highly power for LVO-AIS, improving outcomes in 1 of every 2 patients. IVT alone provides benefit in 1 in 5 patients.