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Background: Neoadjuvant association of immune checkpoints inhibitors (ICI) and dose dense chemotherapy is promising for triple negative breast cancers (TNBC). However, response rates vary from one study to another. Timing, best chemotherapy partner and efficacy in less immunogenic breast cancer (BC), like luminal B tumors, should be further investigated. This study evaluates for TNBC and luminal B HER2(-) BC the neoadjuvant treatment with paclitaxel followed by a short combination of an anti-PD-L1 antibody with anthracyclines. Method B-IMMUNE (NCT03356860), a multicentric phase Ib/II prospective trial, included patients with stage I to III luminal B HER2(-) or TNBC treated with paclitaxel 80mg/m2 weekly from week 1 to 12 followed by 4 cycles of epirubicine 90mg/m2 and cyclophosphamide 600 mg/m2 (EC) Q2W in a neoadjuvant setting. Phase Ib evaluated a single infusion of durvalumab (anti-PD-L1) combined with the 3rd cycle of EC. Phase II evaluated infusions of durvalumab with the 1st and 3rd EC cycles. Surgery was planned 3 weeks after the last EC cycle. Primary objectives were safety and pathological complete response (pCR) rate compared to a historical control. Secondary endpoint was the overall response rate (ORR) based on breast MRI. Eleven patients were enrolled in a control arm without durvalumab, exclusively for translational research purposes. Based on a 2-stage Simon design with an α = 0.1 and β = 0.1, 22 TNBC patients were needed in the phase II to test a null hypothesis of 30% pCR rate against a one-side alternative of 60%, and 24 luminal B BC patients to test a null hypothesis of 15% pCR rate against a one-side alternative of 40% (including an additional accrual margin of 10% for eventual dropouts). At least 9 pCRs had to be observed among the first 20 evaluable TNBC patients and 6 among the first 22 evaluable luminal B patients to rule out the null hypothesis. Results This analysis concerns the 50 patients treated with the experimental treatment, 3 from the phase Ib and 47 from the phase II part. Median age was 51 y-old (31 to 72y), tumor subtypes were 24 TNBC, 25 Luminal B and one sarcoma excluded from the efficacy analysis. Seven (14%) patients had a stage I tumor, 17 (34%) a stage IIA, 13 (26%) a stage IIB, 8 (16%) a stage IIIA, 4 (8%) a stage IIIB and 1 (2%) a stage IIIC. Concerning safety, 232 AEs were reported on 39/50 patients and 34 (14,6%) were graded ≥ 3. The 5 most frequent all-grade AEs were fatigue (8,2%), diarrhea (5,6%), neutropenia (5,2%), anemia and nausea (4,3%). Most frequent grade 3 AEs were anemia and neutropenia (14,7%). Among 4 immune-related adverse events, all were thyroid disorders. One patient died 10 months after the end of treatment due to progressive disease in the liver. Forty-six of the 47 phase II patients were evaluable for efficacy. pCR was reported in 12/22 TNBC patients (55%) and 8/24 luminal B HER2(-) patients (33%). Subgroup analyses based on PD-L1 expression and TILs score are planned. Conclusions The B-IMMUNE study met its primary objective showing a significant improvement in pCR versus the historical control in both TNBC and in Luminal B HER2(-) BC cohorts with the addition of only 2 doses of durvalumab to the anthracyclines. The safety profile is comparable to those previously described with reported immune related adverse events limited to thyroid endocrine disorders. Citation Format: Alix Devaux, Gabriela Beniuga, Claire Quaghebeur, Stéphanie Henry, Mieke Van Bockstal, Christine Galant, Paul Delrée, Jean-Luc Canon, Brigitte Honhon, Dominique Korman, Vincent Verschaeve, Christophe Lonchay, Sarah Lefevre, Lionel D’Hondt, Martine Berlière, Sophie Delmarcelle, Jean-Michel Mine, Timour Willems, Gebhard Müller, Nathalie Myant, Isabelle Bar, Sandy Haussy, Pierre G. Coulie, François P. Duhoux, Javier Carrasco. B-IMMUNE final analysis: a phase Ib/II study of durvalumab combined with dose-dense EC in a neoadjuvant setting for patients with locally advanced luminal B HER2(-) or triple negative breast cancers. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-16.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has been widely used in patients with COVID-19, but uncertainty remains about the determinants of in-hospital mortality and data on post-discharge outcomes are scarce. The aims of this study were to investigate the variables associated with in-hospital outcomes in patients who received ECMO during the first wave of COVID-19 and to describe the status of patients 6 months after ECMO initiation.METHODS: EuroECMO-COVID is a prospective, multicentre, observational study developed by the European Extracorporeal Life Support Organization. This study was based on data from patients aged 16 years or older who received ECMO support for refractory COVID-19 during the first wave of the pandemic-from March 1 to Sept 13, 2020-at 133 centres in 21 countries. In-hospital mortality and mortality 6 months after ECMO initiation were the primary outcomes. Mixed-Cox proportional hazards models were used to investigate associations between patient and management-related variables (eg, patient demographics, comorbidities, pre-ECMO status, and ECMO characteristics and complications) and in-hospital deaths. Survival status at 6 months was established through patient contact or institutional charts review. This study is registered with ClinicalTrials.gov, NCT04366921, and is ongoing.FINDINGS: Between March 1 and Sept 13, 2020, 1215 patients (942 [78%] men and 267 [22%] women; median age 53 years [IQR 46-60]) were included in the study. Median ECMO duration was 15 days (IQR 8-27). 602 (50%) of 1215 patients died in hospital, and 852 (74%) patients had at least one complication. Multiorgan failure was the leading cause of death (192 [36%] of 528 patients who died with available data). In mixed-Cox analyses, age of 60 years or older, use of inotropes and vasopressors before ECMO initiation, chronic renal failure, and time from intubation to ECMO initiation of 4 days or more were associated with higher in-hospital mortality. 613 patients did not die in hospital, and 547 (95%) of 577 patients for whom data were available were alive at 6 months. 102 (24%) of 431 patients had returned to full-time work at 6 months, and 57 (13%) of 428 patients had returned to part-time work. At 6 months, respiratory rehabilitation was required in 88 (17%) of 522 patients with available data, and the most common residual symptoms included dyspnoea (185 [35%] of 523 patients) and cardiac (52 [10%] of 514 patients) or neurocognitive (66 [13%] of 512 patients) symptoms.INTERPRETATION: Patient's age, timing of cannulation (FUNDING: None.

The efficacy and safety of primary re-irradiation for MSCC are not known. Our aim was to establish the efficacy and safety of biologically effective dose-based re-irradiation.Patients presenting with MSCC at a previously irradiated spine segment, and not proceeding with surgical decompression, were eligible. A 3 Gray per fraction experimental schedule (minimum 18 Gy/6 fractions, maximum 30 Gy/10 fractions) was used, delivering a maximum cumulative spinal dose of 100 GyTwenty-two patients were enroled, of whom eleven were evaluable for the primary outcome. Nine of eleven (81.8%) had stable or improved Tomita scores at 5 weeks. One of eight (12.5%) evaluable for late toxicity developed RIM.Re-irradiation is an efficacious treatment for MSCC. There is a risk of RIM with a cumulative dose of 120 GyCancer Trials Ireland (ICORG 07-11); NCT00974168.

Active rock glaciers are among the most common cryospheric landforms in high-altitude mid-latitude mountain ranges. Over both short (years to decades) to long (centuries to millennia) time scales, their activity strongly influences the hydrology and geomorphology of alpine environments. Consequently, rock glaciers reflect paleoclimatic conditions and can be seen as an important player in erosion processes affecting high mountains slopes. Because they represent a visible expression of mountain permafrost and a considerable water reserve in the form of ground ice, rock glaciers are important landforms in the geomorphological and hydrological evolution of mountain systems, particularly in context of climate crisis. However, our understanding of rock glacier dynamics and its evolution at different time scales still need to be improved.In this study, we present a multi-method approach, including field observations, remote sensing and geochronology, to study the rock glacier system of the Vallon de la Route (Combeynot Massif, western French Alps). Remote sensing images and correlation techniques are used to document the rock glacier movement field on time scales ranging from days to decades. In addition, to estimate displacement over periods ranging from centuries to millennia, we use surface exposure dating with terrestrial cosmogenic nuclides (10Be quartz) on boulder surfaces along the longitudinal line of the rock glacier, targeting different positions from the headwall to the terminus.The remote sensing analysis processed between 1960 and 2018 agree with the geomorphological observations: the lower two units of the rock glacier are stationary/relict, the transition unit presents small displacement and not over its entire area, and the upper two active units above 2600 m elevation show integrated velocities between 14 and 15 cm a-1. 10Be surface exposure ages are ranging from 13.10 ± 0.51 to 1.88 ± 0.14 ka and their spatial distribution reveals an inverse first-order correlation between surface exposure age and elevation, and a positive correlation with horizontal distance to the headwall. These observations support the hypothesis that boulders fall from the headwall and remain on the surface of the rock glacier as they are transported down the valley. Our results also suggest that the rock glacier is characterized by two major phases of activity. The first phase, beginning around 12 ka, has a 10Be age gradient, following a quiet period between ~6.2 and 3.4 ka prior to the emplacement of the two present-day upper active units. Rock glacier started to be active again by 3.4 ka and still is now above 2600 m a.s.l. These results allow to quantify headwall erosion rates of between 1.0 and 2.5 mm a-1, greater than the watershed-integrated denudation rates estimated on millennial time scales. This suggests that the rock glacier system supports the maintenance of high rock wall erosion by acting as a conveyor of debris and allowing freshly exposed bedrock surfaces to be affected by erosional processes.

International audience; This study tests the application of combined detrital apatite fission track (AFT) and U-Pb dating to infer both glacial erosion spatial patterns and long-term rock cooling histories in Alpine mountainous settings. We have dated 716 detrital apatite grains from glacial sediments collected in the Maurienne and Arve valleys (Western European Alps, France) from moraine deposits corresponding to different stages of glacial retreat since the Last Glacial Maximum (LGM, ca. 24-21 ka).The Maurienne valley crosses the internal and external Alps, which exhibit contrasting in-situ AFT and U-Pb ages. Here, we present the measured distribution of both detrital AFT and U-Pb ages at 6 locations along the valley, with catchment elevations ranging from 390 to 1740 m. We show that during glacial retreat, erosion is mainly concentrated in the downstream part of the glacier, near the sampled moraine deposits. This inference suggests that during glacial retreat, glacial erosion is more effective below the ELA (Equilibrium Line Altitude) and specifically close to the glacier front, in areas where ice flow velocity is high and subglacial water is abundant, as predicted by ice-dynamics reconstructions in the European Alps over the last 20 ka.In the Arve valley, previous studies showed that in situ AFT ages are systematically younger than 7 Ma for the Mont-Blanc massif. We compare the thermal history obtained from these literature bedrock-derived data to that derived from the new detrital AFT data collected in the Little Ice Age (LIA) moraine, just at the front of the Bossons glacier (~1300 m elevation). We also compare our results with 5 other samples down the valley at catchment elevations between 460 and 1050 m to evaluate potential changes in the detrital AFT signal as well as the consistency in the retrieved long-term cooling history.Based on these first results, we plan to extend our study to other areas (e.g., Patagonia) to investigate both (1) spatial patterns of glacial erosion for older glacial periods (pre-LGM), and (2) long-term rock cooling histories from moraine deposits where modern bedrock is inaccessible (e.g. under modern glaciers or ice fields).

Supplementary Figure legends

Figure S1 shows the numbers of dendritic cells, macrophages and B cells in the colon, and the numbers of dendritic cells in the mesenteric lymph nodes of control and cKO mice treated with AOM and DSS.

The escape of cancer cells from host immunosurveillance involves a shift in immune responses, including an imbalance in Th1 and Th2 cells. A Th1-dominated immune response predicts positive outcomes in colorectal cancer. The E3 ubiquitin ligase, Asb2α, is expressed in Th2 cells, but its roles in T-cell maturation and cancer are unclear. We provide evidence that the Th2 master regulator, Gata3, induces Asb2. Loss of Asb2 did not affect Th differentiation ex vivo, but reduced IL4 production from Th2 cells. We found that high ASB2 expression was associated with poor outcome in colorectal cancer. Loss of Asb2 from hematopoietic cells promoted a Th1 response and attenuated colitis-associated tumorigenesis in mice. Diminished Th2 function correlated with increased IFNγ production and an enhanced type 1 antitumor immune response in Asb2-deficient mice. Our work suggests that Asb2α promotes a Th2 phenotype in vivo, which in turn is associated with tumor progression in a mouse model of colitis.