Immunologic response to the survivin-derived multi-epitope vaccine EMD640744 in patients with advanced solid tumors

PURPOSE Survivin is a member of the inhibitor-of-apoptosis family. Essential for tumor cell survival and overexpressed in most cancers, survivin is a promising target for anti-cancer immunotherapy. Immunogenicity has been demonstrated in multiple cancers. Nonetheless, few clinical trials have demonstrated survivin-vaccine-induced immune responses. EXPERIMENTAL DESIGN This phase I trial was conducted to test whether vaccine EMD640744, a cocktail of five HLA class I-binding survivin peptides in Montanide(®) ISA 51 VG, promotes anti-survivin T-cell responses in patients with solid cancers. The primary objective was to compare immunologic efficacy of EMD640744 at doses of 30, 100, and 300 μg. Secondary objectives included safety, tolerability, and clinical efficacy. RESULTS In total, 49 patients who received ≥2 EMD640744 injections with available baseline- and ≥1 post-vaccination samples [immunologic-diagnostic (ID)-intention-to-treat] were analyzed by ELISpot- and peptide/MHC-multimer staining, revealing vaccine-activated peptide-specific T-cell responses in 31 patients (63 %). This cohort included the per study protocol relevant ID population for the primary objective, i.e., T-cell responses by ELISpot in 17 weeks following first vaccination, as well as subjects who discontinued the study before week 17 but showed responses to the treatment. No dose-dependent effects were observed. In the majority of patients (61 %), anti-survivin responses were detected only after vaccination, providing evidence for de novo induction. Best overall tumor response was stable disease (28 %). EMD640744 was well tolerated; local injection-site reactions constituted the most frequent adverse event. CONCLUSIONS Vaccination with EMD640744 elicited T-cell responses against survivin peptides in the majority of patients, demonstrating the immunologic efficacy of EMD640744.

The ARCH Projects: design and rationale (IAASSG 001).

OBJECTIVE A number of factors limit the effectiveness of current aortic arch studies in assessing optimal neuroprotection strategies, including insufficient patient numbers, heterogenous definitions of clinical variables, multiple technical strategies, inadequate reporting of surgical outcomes and a lack of collaborative effort. We have formed an international coalition of centres to provide more robust investigations into this topic. METHODS High-volume aortic arch centres were identified from the literature and contacted for recruitment. A Research Steering Committee of expert arch surgeons was convened to oversee the direction of the research. RESULTS The International Aortic Arch Surgery Study Group has been formed by 41 arch surgeons from 10 countries to better evaluate patient outcomes after aortic arch surgery. Several projects, including the establishment of a multi-institutional retrospective database, randomized controlled trials and a prospectively collected database, are currently underway. CONCLUSIONS Such a collaborative effort will herald a turning point in the surgical management of aortic arch pathologies and will provide better powered analyses to assess the impact of varying surgical techniques on mortality and morbidity, identify predictors for neurological and operative risk, formulate and validate risk predictor models and review long-term survival outcomes and quality-of-life after arch surgery.

Who Earns More and Why? A Multiple Mediation Model from Personality to Salary

Purpose The purpose of this study was to investigate multiple indirect Big Five personality influences on professionals’ annual salary while considering relevant mediators. These are the motivational variables of occupational self-efficacy and career-advancement goals, and the work status variable of contractual work hours. The motivational and work status variables were conceptualized as serial mediators (Big Five → occupational self-efficacy/career-advancement goals → contractual work hours → annual salary). Design/Methodology/Approach We realized a 4 year longitudinal survey study with 432 participants and three points of measurement. We assessed personality prior to the mediators and the mediators prior to annual salary. Findings Results showed that except for openness the other Big Five personality traits exerted indirect influences on annual salary. Career-advancement goals mediated influences of conscientiousness (+), extraversion (+), and agreeableness (−). Occupational self-efficacy mediated influences of neuroticism (–) and conscientiousness (+). Because the influence of occupational self-efficacy on annual salary was fully mediated by contractual work hours, indirect personality influences via occupational self-efficacy always included contractual work hours in a serial mediation. Implications These findings underline the importance of distal personality traits for career success. They give further insights into direct and indirect relationships between personality, goal content, self-efficacy beliefs, and an individual’s career progress. Originality/Value Previous research predominantly investigated direct Big Five influences on salary, and it analyzed cross-sectional data. This study is one of the first to investigate multiple indirect Big Five influences on salary in a longitudinal design. The findings support process-oriented theories of personality influences on career outcomes.

Home-based training to improve manual dexterity in patients with multiple sclerosis: A randomized controlled trial.

BACKGROUND Impaired manual dexterity is frequent and disabling in patients with multiple sclerosis (MS), affecting activities of daily living (ADL) and quality of life. OBJECTIVE We aimed to evaluate the effectiveness of a standardized, home-based training program to improve manual dexterity and dexterity-related ADL in MS patients. METHODS This was a randomized, rater-blinded controlled trial. Thirty-nine MS patients acknowledging impaired manual dexterity and having a pathological Coin Rotation Task (CRT), Nine Hole Peg Test (9HPT) or both were randomized 1:1 into two standardized training programs, the dexterity training program and the theraband training program. Patients trained five days per week in both programs over a period of 4 weeks. Primary outcome measures performed at baseline and after 4 weeks were the CRT, 9HPT and a dexterous-related ADL questionnaire. Secondary outcome measures were the Chedoke Arm and Hand Activity Inventory (CAHAI-8) and the JAMAR test. RESULTS The dexterity training program resulted in significant improvements in almost all outcome measures at study end compared with baseline. The theraband training program resulted in mostly non-significant improvements. CONCLUSION The home-based dexterity training program significantly improved manual dexterity and dexterity-related ADL in moderately disabled MS patients. Trial Registration NCT01507636.

A steerable UV laser system for the calibration of liquid argon time projection chambers

A number of liquid argon time projection chambers (LAr TPCs) are being built or are proposed for neutrino experiments on long- and short baseline beams. For these detectors, a distortion in the drift field due to geometrical or physics reasons can affect the reconstruction of the events. Depending on the TPC geometry and electric drift field intensity, this distortion could be of the same magnitude as the drift field itself. Recently, we presented a method to calibrate the drift field and correct for these possible distortions. While straight cosmic ray muon tracks could be used for calibration, multiple coulomb scattering and momentum uncertainties allow only a limited resolution. A UV laser instead can create straight ionization tracks in liquid argon, and allows one to map the drift field along different paths in the TPC inner volume. Here we present a UV laser feed-through design with a steerable UV mirror immersed in liquid argon that can point the laser beam at many locations through the TPC. The straight ionization paths are sensitive to drift field distortions, a fit of these distortion to the linear optical path allows to extract the drift field, by using these laser tracks along the whole TPC volume one can obtain a 3D drift field map. The UV laser feed-through assembly is a prototype of the system that will be used for the MicroBooNE experiment at the Fermi National Accelerator Laboratory (FNAL).

Multiple programmed cell death pathways are involved in N-methyl-N-nitrosourea-induced photoreceptor degeneration.

PURPOSE: To identify programmed cell death (PCD) pathways involved in N-methyl-N-nitrosourea (MNU)-induced photoreceptor (PR) degeneration. METHODS: Adult C57BL/6 mice received a single MNU i.p. injection (60 mg/kg bodyweight), and were observed over a period of 7 days. Degeneration was visualized by H&E overview staining and electron microscopy. PR cell death was measured by quantifying TUNEL-positive cells in the outer nuclear layer (ONL). Activity measurements of key PCD enzymes (calpain, caspases) were used to identify the involved cell death pathways. Furthermore, the expression level of C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78), key players in endoplasmic reticulum (ER) stress-induced apoptosis, was analyzed using quantitative real-time PCR. RESULTS: A decrease in ONL thickness and the appearance of apoptotic PR nuclei could be detected beginning 3 days post-injection (PI). This was accompanied by an increase of TUNEL-positive cells. Significant upregulation of activated caspases (3, 9, 12) was found at different time periods after MNU injection. Additionally, several other players of nonconventional PCD pathways were also upregulated. Consequently, calpain activity increased in the ONL, with a maximum on day 7 PI and an upregulation of CHOP and GRP78 expression beginning on day 1 PI was found. CONCLUSIONS: The data indicate that regular apoptosis is the major cause of MNU-induced PR cell death. However, alternative PCD pathways, including ER stress and calpain activation, are also involved. Knowledge about the mechanisms involved in this mouse model of PR degeneration could facilitate the design of putative combinatory therapeutic approaches.

Addressing Multilevel Program Complexity by Evaluation Design

In this paper, we present the evaluation design for a complex multilevel program recently introduced in Switzerland. The evaluation embraces the federal level, the cantonal program level, and the project level where target groups are directly addressed. We employ Pawson and Tilley’s realist evaluation approach, in order to do justice to the varying context factors that impact the cantonal programs leading to varying effectiveness of the implemented activities. The application of the model to the canton of Uri shows that the numerous vertical and horizontal relations play a crucial role for the program’s effectiveness. As a general learning for the evaluation of complex programs, we state that there is a need to consider all affected levels of a program and that no monocausal effects can be singled out in programs where multiple interventions address the same problem. Moreover, considering all affected levels of a program can mean going beyond the borders of the actual program organization and including factors that do not directly interfere with the policy delivery as such. In particular, we found that the relationship between the cantonal and the federal level was a crucial organizational factor influencing the effectiveness of the cantonal program.

Scheduled versus Pro Re Nata Dosing in the VIEW Trials

PURPOSE To analyze visual acuity (VA) outcomes before and after preplanned treatment regimen change in the VIEW studies at week 52 (W52). DESIGN Multiple post hoc analyses for retrospectively defined subgroups in 2 multicenter, multinational, double-masked trials. PARTICIPANTS Two thousand four hundred fifty-seven neovascular age-related macular degeneration (AMD) patients. METHODS Patients were randomized to treatment with 0.5 mg ranibizumab given monthly, a 0.5-mg or 2-mg intravitreal aflibercept injection given monthly, or 2 mg intravitreal aflibercept given every other month, after 3 initial monthly doses, up to W52. From W52 through W96, patients received their original dosing assignment using a capped pro re nata (PRN) regimen, with defined retreatment criteria based on VA and morphologic signs of disease activity and mandatory dosing at least every 12 weeks. MAIN OUTCOME MEASURES Best-corrected VA (BCVA) and optical coherence tomography assessments were mandatory at all visits from baseline to W96. Outcomes were changes in BCVA and central retinal thickness. Outcomes were evaluated in all patients who completed 2 years of the VIEW studies using the last observation carried forward method for missing data at interim visits. RESULTS After W52, approximately 20% of patients lost 5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters or more across all treatment arms with PRN treatment. Patients who met the retreatment criterion of loss of 5 ETDRS letters or more in the first quarter of the PRN dosing phase did not recover; mean final VA loss across the 4 study arms was -4.4 to -5.8 letters. Outcomes of these patients up to W52 were indistinguishable from those of the overall population. There were no differences between groups in serious ocular adverse events or Anti-Platelet Trialists' Collaboration arterial thromboembolic events through W96. CONCLUSIONS These analyses suggest that there are subgroups of patients for whom VA outcomes in the second year of the VIEW studies were less stable than in the first year and for whom W52 seems to be an important inflection point. Although alternate reasons specific to the nature of the underlying AMD cannot be fully excluded, the switch in treatment regimen at W52 is a plausible explanation.

Usability and Acceptability of ASSESS MS: Assessment of Motor Dysfunction in Multiple Sclerosis Using Depth-Sensing Computer Vision

Background: Sensor-based recordings of human movements are becoming increasingly important for the assessment of motor symptoms in neurological disorders beyond rehabilitative purposes. ASSESS MS is a movement recording and analysis system being developed to automate the classification of motor dysfunction in patients with multiple sclerosis (MS) using depth-sensing computer vision. It aims to provide a more consistent and finer-grained measurement of motor dysfunction than currently possible. Objective: To test the usability and acceptability of ASSESS MS with health professionals and patients with MS. Methods: A prospective, mixed-methods study was carried out at 3 centers. After a 1-hour training session, a convenience sample of 12 health professionals (6 neurologists and 6 nurses) used ASSESS MS to capture recordings of standardized movements performed by 51 volunteer patients. Metrics for effectiveness, efficiency, and acceptability were defined and used to analyze data captured by ASSESS MS, video recordings of each examination, feedback questionnaires, and follow-up interviews. Results: All health professionals were able to complete recordings using ASSESS MS, achieving high levels of standardization on 3 of 4 metrics (movement performance, lateral positioning, and clear camera view but not distance positioning). Results were unaffected by patients’ level of physical or cognitive disability. ASSESS MS was perceived as easy to use by both patients and health professionals with high scores on the Likert-scale questions and positive interview commentary. ASSESS MS was highly acceptable to patients on all dimensions considered, including attitudes to future use, interaction (with health professionals), and overall perceptions of ASSESS MS. Health professionals also accepted ASSESS MS, but with greater ambivalence arising from the need to alter patient interaction styles. There was little variation in results across participating centers, and no differences between neurologists and nurses. Conclusions: In typical clinical settings, ASSESS MS is usable and acceptable to both patients and health professionals, generating data of a quality suitable for clinical analysis. An iterative design process appears to have been successful in accounting for factors that permit ASSESS MS to be used by a range of health professionals in new settings with minimal training. The study shows the potential of shifting ubiquitous sensing technologies from research into the clinic through a design approach that gives appropriate attention to the clinic environment.

Statistical testing against baseline was common in dental research

OBJECTIVES To assess the presence of within-group comparisons with baseline in a subset of leading dental journals and to explore possible associations with a range of study characteristics including journal and study design. STUDY DESIGN AND SETTING Thirty consecutive issues of five leading dental journals were electronically searched. The conduct and reporting of statistical analysis in respect of comparisons against baseline or otherwise along with the manner of interpretation of the results were assessed. Descriptive statistics were obtained, and chi-square test and Fisher's exact were undertaken to test the association between trial characteristics and overall study interpretation. RESULTS A total of 184 studies were included with the highest proportion published in Journal of Endodontics (n = 84, 46%) and most involving a single center (n = 157, 85%). Overall, 43 studies (23%) presented interpretation of their outcomes based solely on comparisons against baseline. Inappropriate use of baseline testing was found to be less likely in interventional studies (P < 0.001). CONCLUSION Use of comparisons with baseline appears to be common among both observational and interventional research studies in dentistry. Enhanced conduct and reporting of statistical tests are required to ensure that inferences from research studies are appropriate and informative.