Paper Session II-B - Phase I Lessons for the New Era

The Shuttle-Mir Program, officially known as the Phase 1 Program, was the premier international human space flight program. It involved 9 docking flights of the Space Shuttle to the Russian Mir Space Station, 7 long duration stays by US crew on the Mir, almost 1000 days of US crew occupancy of the Mir, and numerous scientific and engineering research activities. Phase 1 was also the source of numerous lessons learned that are being applied to the International Space Station to improve its safety, efficiency, and productivity as a research facility. These include learning to work with an international partner, improvements to experiment design and planning, hardware design risk mitigation, and first hand experience handling many of the most critical safety and operational issues confronting a space station. This paper will briefly cover the major contributions of the Phase 1 Program to ISS and subsequent cooperative space ventures

Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls

Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group

Funder: U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)Funder: National Center for Research Resources under award number 1 C06 RR12463-01, VA Merit Review Award IBX004121A from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the DOD Prostate Cancer Idea Development Award (W81XWH-15-1-0558), the DOD Lung Cancer Investigator-Initiated Translational Research Award (W81XWH-18-1-0440), the DOD Peer Reviewed Cancer Research Program (W81XWH-16-1-0329), the Ohio Third Frontier Technology Validation Fund, the Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering and the Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University.Funder: Susan G Komen Foundation (CCR CCR18547966) and a Young Investigator Grant from the Breast Cancer Alliance.Funder: The Canadian Cancer SocietyFunder: Breast Cancer Research Foundation (BCRF), Grant No. 17-194Abstract: Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring

Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Funder: Breast Cancer Research Foundation (BCRF); doi: https://doi.org/10.13039/100001006Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting

An electrochemical and SEM study of the mechanism of formation, morphology, and composition of titanium or zirconium fluoride-based coatings

International audienceElectrochemical rest potential and cyclic voltametry were used to investigate the behaviour of the 6% Al magnesium alloy AM60 in various zirconium or titanium fluoride aqueous acid solutions. These solutions have a wide range of aggressiveness with respect to AM60 due largely to fluoride concentration and in some cases to their highly acidic nature. The morphology and composition of the resulting film have been determined by Scanning Electron Microscopy (SEM), and Energy Dispersive X-ray spectroscopy (EDX). The film nucleation is promoted by a pH increase due to water reduction and is thus more likely to occur on the cathodic parts of the surface. Correlatively, film formation on the anodic primary solid solution occurred in only one solution

Monochromatized x-ray photoelectron spectroscopy of the AM60 magnesium alloy surface after treatments in fluoride-based Ti and Zr solutions

International audienceThe behaviour of the 6% aluminium-magnesium alloy (AM60) surface in zirconium or titanium fluoride aqueous acid solutions was studied. X-ray photoelectron spectroscopy was used to investigate modifications in the surface chemistry with respect to the composition of the surface treatment solution. The surface film is composed of magnesium hydroxide and hydroxyfluoride, zirconium oxide, oxyhydroxide or oxyfluoride, titanium oxide and structural and adsorbed water. Optimal parameters leading to the formation of a zirconium- or titanium-rich film were determined. A mechanism is proposed for the formation of zirconium- or titanium-based films

The surface reactivity of a magnesium–aluminium alloy in acidic fluoride solutions studied by electrochemical techniques and XPS

International audienceThe behaviour of the 6% Al magnesium alloy AM60 in aqueous acid fluoride solutions was studied in situ by electrochemical techniques and the surface chemistry of the resulting film was examined by monochromatized XPS. The evolution of the corrosion potential and cyclic voltammograms showed that the aggressiveness of the solutions is mainly driven by their fluoride concentration, the pH having almost no detectable influence. The more concentrated and acidic fluoride solutions led to a higher degree of fluoride coverage of the surface. The surface film is composed of magnesium hydroxide and hydroxyfluoride Mg(OH)2−xFx which approaches MgF2 with increasing fluoride concentration in the film. The parameters governing the film evolution and their relation to surface reactions are discussed

Analysis of In-Space Assembly of Modular Systems

Early system-level life cycle assessments facilitate cost effective optimization of system architectures to enable implementation of both modularity and in-space assembly, two key Exploration Systems Research & Technology (ESR&T) Strategic Challenges. Experiences with the International Space Station (ISS) demonstrate that the absence of this rigorous analysis can result in increased cost and operational risk. An effort is underway, called Analysis of In-Space Assembly of Modular Systems, to produce an innovative analytical methodology, including an evolved analysis toolset and proven processes in a collaborative engineering environment, to support the design and evaluation of proposed concepts. The unique aspect of this work is that it will produce the toolset, techniques and initial products to analyze and compare the detailed, life cycle costs and performance of different implementations of modularity for in-space assembly. A multi-Center team consisting of experienced personnel from the Langley Research Center, Johnson Space Center, Kennedy Space Center, and the Goddard Space Flight Center has been formed to bring their resources and experience to this development. At the end of this 30-month effort, the toolset will be ready to support the Exploration Program with an integrated assessment strateg