Design Optimisation and Mass Saving of the Structure of the Orion-MPCV European Service Module

This paper presents an overview of the design optimisation measures that have been proposed and analysed in order to reduce the mass of the structure, including the MMOD (Micro-Meteoroid and Orbital Debris) protection system, of the ESM (European Service Module) for the Orion MPCV (Multi-Purpose Crew Vehicle). Under an agreement between NASA and ESA, the NASA Orion MPCV for human space exploration missions will be powered by a European Service Module, based on the design and experience of the ATV (Automated Transfer Vehicle). The development and qualification of the European Service Module is managed and implemented by ESA. The ESM prime contractor and system design responsible is Airbus Defence and Space. Thales Alenia Space Italia is responsible for the design and integration of the ESM Structure and MMOD protection system in addition to the Thermal Control System and the Consumable Storage System. The Orion Multi-Purpose Crew Vehicle is a pressurized, crewed spacecraft that transports up to four crew members from the Earths surface to a nearby destination or staging point. Orion then brings the crew members safely back to the Earths surface at the end of the mission. Orion provides all services necessary to support the crew members while on-board for short duration missions (up to 21 days) or until they are transferred to another orbiting habitat. The ESM supports the crew module from launch through separation prior to re-entry by providing: in-space propulsion capability for orbital transfer, attitude control, and high altitude ascent aborts; water and oxygen/nitrogen needed for a habitable environment; and electrical power generation. In addition, it maintains the temperature of the vehicle's systems and components and offers space for unpressurized cargo and scientific payloads. The ESM has been designed for the first 2 Lunar orbit missions, EM-1 (Exploration mission 1) is an un-crewed flight planned around mid-2020, and EM-2, the first crewed flight, is planned in 2022. At the time where the first ESM is about to be weighted, the predicted mass lies slightly above the initial requirement. For future builds, mass reduction of the Service Module has been considered necessary. This is being investigated, together with other design improvements, in order to consolidate the ESM design and increase possible future missions beyond the first two Orion MPCV missions. The mass saving study has introduced new optimised structural concepts, optimisation of the MMOD protection shields, and optimised redesign of parts for manufacturing through AM (Additive Manufacturing)

Treatments after Immune Checkpoint Inhibitors in Patients with dMMR/MSI Metastatic Colorectal Cancer

International audienceBackground: Several studies reported improved outcomes with conventional treatments (CT, i.e., chemotherapy ± targeted therapy) administered after immune checkpoints inhibitors (ICI) in certain tumor types. No data are available concerning patients (pts) with metastatic colorectal cancer (mCRC) harboring mismatch repair deficiency/microsatellite instability (dMMR/MSI). We aimed to assess the outcomes of dMMR/MSI mCRC pts receiving CT after ICI failure.Methods: We conducted a retrospective multicenter study investigating the outcomes of all dMMR/MSI mCRC pts who received post-ICI CT between 2015 and 2020.Results: 31 pts (male 61%, median age 56 years) were included. ICI was an anti-PD(L)1 monotherapy in 71% of pts, and 61% received >2 lines before post-ICI CT. The overall response rate and disease control rate were 13% and 45%, with a median progression-free survival (PFS) and overall survival of 2.9 and 7.4 months, respectively. No association of the outcomes with either ICI efficacy or anti-angiogenic agents was observed. Prolonged PFS (range 16.1-21.3 months) was observed in 4 pts (13%).Conclusions: Although conducted on a limited number of patients, our results do not support an association of previous ICI treatment with an enhanced efficacy of CT in dMMR/MSI mCRC. However, prolonged disease control was observed in several cases, suggesting that some pts might derive an unexpected benefit from post-ICI treatments

A multicenter study evaluating efficacy of immune checkpoint inhibitors in advanced non-colorectal digestive cancers with microsatellite instability

Background: One randomized phase III trial comparing chemotherapy (CT) with immune checkpoint inhibitors (ICI) has demonstrated significant efficacy of ICI in deficient DNA mismatch repair system/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer. However, few studies have compared ICI with CT in other advanced dMMR/MSI-H digestive tumors. Methods: In this multicenter study, we included patients with advanced dMMR/MSI-H non-colorectal digestive tumors treated with chemotherapy and/or ICIs. Patients were divided retrospectively into two groups, a CT group and an immunotherapy (IO) group. The primary endpoint was progression-free survival (PFS). A propensity score approach using the inverse probability of treatment weighting (IPTW) method was applied to deal with potential differences between the two groups. Results: 133 patients (45.1/27.1/27.8% with gastric/small bowel/other carcinomas) were included. The majority of patients received ICI in 1st (29.1%) or 2nd line (44.4%). The 24-month PFS rates were 7.9% in the CT group and 71.2% in the IO group. Using the IPTW method, IO treatment was associated with better PFS (HR=0.227; 95% CI 0.147–0.351; p < 0.0001). The overall response rate was 26.3% in the CT group versus 60.7% in the IO group (p < 0.001) with prolonged duration of disease control in the IO group (p < 0.001). In multivariable analysis, predictive factors of PFS for patients treated with IO were good performance status, absence of liver metastasis and prior primary tumor resection, whereas no association was found for the site of the primary tumor. Conclusions: In the absence of randomized trials, our study highlights the superior efficacy of ICI compared with standard-of-care therapy in patients with unresectable or metastatic dMMR/MSI-H non-colorectal digestive cancer, regardless of tumor type, with acceptable toxicity.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Efficacy of immunotherapy in mismatch repair-deficient advanced colorectal cancer in routine clinical practice. An AGEO study

Background: Immunotherapy demonstrated remarkable efficacy in metastatic colorectal cancers (mCRCs) with mismatch repair deficiency (MMRd)/microsatellite instability (MSI). However, data regarding efficacy and safety of immunotherapy in the routine clinical practice are scarce. Patients and methods: This is a retrospective, multicenter study aiming to evaluate efficacy and safety of immunotherapy in routine clinical practice and to identify predictive markers for long-term benefit. Long-term benefit was defined as progression-free survival (PFS) exceeding 24 months. All patients who received immunotherapy for an MMRd/MSI mCRC were included. Patients who received immunotherapy in combination with another known effective therapeutic class agent (chemotherapy or tailored therapy) were excluded. Results: Overall, 284 patients across 19 tertiary cancer centers were included. After a median follow-up of 26.8 months, the median overall survival (mOS) was 65.4 months [95% confidence interval (CI) 53.8 months-not reached (NR)] and the median PFS (mPFS) was 37.9 months (95% CI 30.9 months-NR). There was no difference in terms of efficacy or toxicity between patients treated in the real-world or as part of a clinical trial. Overall, 46.6% of patients had long-term benefit. Independent markers associated with long-term benefit were Eastern Cooperative Oncology Group-performance status (ECOG-PS) 0 (P = 0.025) and absence of peritoneal metastases (P = 0.009). Conclusions: Our study confirms the efficacy and safety of immunotherapy in patients with advanced MMRd/MSI CRC in the routine clinical practice. ECOG-PS score and absence of peritoneal metastases provide simple markers that could help identify patients who benefit the most from this treatment.SCOPUS: ar.jinfo:eu-repo/semantics/publishe