Hydrodynamic identification of NAUTILUS FOWT platform from small scale tests

A small-scale tank test campaign of the NAUTILUS offshore wind floating semisub-mersible platform was held at the Ifremer Deep Water Basin within the framework of the MaRINET 2 project. The support structure consists in four stabilized columns on a square pontoon supporting a generic 8-MW wind turbine. The tests were carried out at 1:36 Froude scale in parked conditions, and the mooring system was modelled as a set of aerial mooring springs providing a nonlinear stiffness. The hydrodynamic characterization of the floater from experimental data was tackled by using traditional techniques in naval architecture), as well as approaches derived from operational modal analysis in the frequency domain, such as the Sub Space Identification—Covariance (SSI-COV) method. The validity of this approach and its potential application to the identification of such kind of structures is discussed against the results of a more traditional technique based on the fitting of decay tests

EP05.02-003 Durvalumab after Chemoradiotherapy (CRT) in Unresectable Stage III NSCLC. Comparative Study of Two Cohorts in the Real-World Setting

[EN] Introduction: Durvalumab is the new standard of care for unresectable locally advanced NSCLC, with PD-L1 _1% and who did not have progression after CRT treatment in the European Union. Our study compares the effectiveness and the frequency of radiation pneumonitis in patients treated with concurrent CRT with or without durvalumab consolidation during the same period in real clinical practice. Methods: A single-center retrospective study. 71 treated patients with unresectable stage III NSCLC were included between March 2018 and December 2021, 37 with CRT followed by durvalumab and 34 with CRT alone. Real-world progression-free survival (rwPFS) and real-world overall survival (rwOS) were calculated since the date of the end CRT. Propensity score matching (PSM) 1:1 was used to account for differences in baseline characteristics. Results: Median age was 67 years (range 46-82). 25.4% of the patients were _75 years old. 78.9% were men and 53.5% former smokers. 54.9% had squamous histology and 28%, 51% and 21% stage IIIA, IIIB and IIIC disease, respectively. The most used scheme was carboplatinpaclitaxel (43.7%), receiving induction chemotherapy in up to 54.9% of patients. 73.2% received between 60-66 Gy doses of radiotherapy. Median time from end of CRT to onset durvalumab was 44 days (range 13-120) with a median of 14 infusions (range 6-27). Of the 34 patients without durvalumab treatment, the expression PD-L1 <1% (58.8%) was the most frequent cause for rejecting consolidation therapy. After PSM analysis, patients distributions were well balanced. With a median follow-up of 19.7 months (range 1.4-36.6); median rw-PFS was 9.3 months (95% CI, 5-13.5) without durvalumab and 17 months (95% CI, 11-22.9) with durvalumab (p¼0.013). Median rw-OS was 19.3 months (95% CI, 3.8-34.8) without durvalumab and 29.9 months (95% CI, 23.3-36.6) with durvalumab (p¼0.241) with a rw-OS% at 6, 18 and 24 months of 90%, 62% and 49% vs 100%, 86% and 74%, respectively. The rate of radiation pneumonitis was more frequent with durvalumab consolidation (56.8% against 44.1%), (p¼0.346), especially within 3 months after CRT. G3 pneumonitis was only observed in the consolidation therapy. Conclusions: Our results demonstrate the effectiveness of durvalumab consolidation after CRT in real-world patients with unresectable stage III NSCLC. Further sample and longer follow-up are required to obtain more accurate results. Active surveillance and appropriate management for radiation pneumonitis are needed, in especially in candidates for consolidation treatmentS

EP05.02-002 Who Benefits More of Durvalumab after Chemoradiotherapy (CRT) in Real-World Patients with Locally Advanced Non-Small-Cell Lung Cancer (NSCLC)?

[EN] Introduction: Durvalumab received EMA approval as consolidation therapy (CT) for unresectable stage III NSCLC with PD-L1 _1% and who did not have progression after CRT. Our objective was to analyze in real clinical practice the effectiveness of durvalumab and explore the clinical factors that may be associated with the benefit from CT. Methods: Retrospective study was made at Hospital of Leon (Spain), including 37 patients with locally advanced NSCLC treated with durvalumab after CRT treatment between March 2018 and october 2021 (40.5% patients were included in the durvalumab early access program). The neutrophil-to-lymphocyte ratio (NLR) could identified after CRT as a factor that may be benefit from durvalumab. Results: Median age was 67 years (range 46-82 years). 40.5% of patients were _70 years old. 78.4% were male and 51.4% smokers. 54% had non-squamous histology. PD-L1 expression was <1% in 5% and not available in 8% patients. 2.7% ROS1 rearrangements, 5.4% KRAS mutations and not available in 43.2% patients. Stage IIIA, IIIB, IIIC disease were 24.3%, 54.1% and 21.6%, respectively. Median time from end of CRT to onset durvalumab was 44 days (range 13-120 days). Overall median CT duration was 214.8 days (range 69-399 days) with a median of 14 infusions (range 6-27 infusions). With a median follow up of 19.7 months (range 1.4-34.9 months); 67.6% had stopped CT: 37.8% due to completing treatment, 16.2% disease progression, 10.8% adverse event and 2.7% due to COVID19 infection. Median real-world progressionfree survival (rwPFS) was 17 months (95% CI, 11-23). Median realworld overall survival (rwOS) was 29.9 months (95% CI, 23.3-36.6). % rwOS at 6, 18 and 24 months were 100%, 86.9% and 74.5%, respectively. For patients with post-CRT NLR not exceeding the cohort median value of 6, receipt of durvalumab was associated with an improvement in rwOS (median not reached vs 25.7 months; p¼0.025). 56.8% patients had any grade of radiation pneumonitis (median time from CRT start: 119 days [range 36-241 days]). Of these, 19% patients developed worsening of radiation pneumonitis with durvalumab. 54,1% developed immune-mediated toxicity, mostly G1-2 (85.1%). Conclusions: Our results demonstrate the effectiveness of durvalumab consolidation in this patients population in a real-life setting. We identified low NLR after CRT as a potentially predictive factor for the benefit of CT in locally advanced NSCLC.S

A global approach to addressing the policy, research and social challenges of male reproductive health

Male infertility is a global health issue; yet to a large extent, our knowledge of its causes, impact and consequence is largely unknown. Recent data indicate that infertile men have an increased risk of somatic disorders such as cancer and die younger compared to fertile men. Moreover, several studies point to a significant adverse effect on the health of the offspring. From the startling lack of progress in male contraception combined with the paucity of improvements in the diagnosis of male infertility, we conclude there is a crisis in male reproductive health. The Male Reproductive Health Initiative has been organized to directly address these issues (www.eshre.eu/Specialty-groups/Special-Interest-Groups/Andrology/MRHI). The Working Group will formulate an evidence-based strategic road map outlining the ways forward. This is an open consortium desiring to engage with all stakeholders and governments

Second Workshop on Atlantic chub mackerel (Scomber colias) (WKCOLIAS2)

The Atlantic chub mackerel Scomber colias has become an increasingly important commercial species in the European Atlantic waters in the last 10–15 years, probably through an expansion process from NW African waters and due to market needs. However, at present there are no assessment or advice requirements. In the WK framework, available information of the species in the West Atlantic waters has been compiled in order to evaluate possible geographical differences and trends, and the feasibility to describe its population structure. Though the Atlantic chub mackerel is not routinely included among the target species in the acoustic surveys performed in the Atlantic Iberian waters and the Mediterranean Sea, a synoptic overview of the species is possible over all its West Atlantic distribution. Moreover, the data available have indicated latitudinal trends, mainly in the landings’ length composition, L50 and the spawning periods. Nevertheless, even if some degree of connectivity likely exists and migrations are occurring between adjacent areas, some subunits could be considered for management purposes. From the assessment models’ trials carried out, the results or reference points obtained for the European fisheries cannot be retained at present. Therefore, continuing collating information from fisheries and biological sampling of the species, obtaining reliable biomass estimations from scientific surveys and identifying management units seem the main priorities to address in future research work and in case of assessment requirements

Causes of hOCT1-dependent cholangiocarcinoma resistance to sorafenib and sensitization by tumor-selective gene therapy

Although the multi-tyrosine kinase inhibitor sorafenib is useful in the treatment of several cancers, cholangiocarcinoma (CCA) is refractory to this drug. Among other mechanisms of chemoresistance, impaired uptake through human organic cation transporter type 1 (hOCT1) (gene SLC22A1) has been suggested. Here we have investigated the events accounting for this phenotypic characteristic and have evaluated the interest of selective gene therapy strategies to overcome this limitation. Gene expression and DNA methylation of SLC22A1 were analyzed using intrahepatic (iCCA) and extrahepatic (eCCA) biopsies (Copenhagen and Salamanca cohorts; n = 132) and The Cancer Genome Atlas (TCGA)-CHOL (n = 36). Decreased hOCT1 mRNA correlated with hypermethylation status of the SLC22A1 promoter. Treatment of CCA cells with decitabine (demethylating agent) or butyrate (histone deacetylase inhibitor) restored hOCT1 expression and increased sorafenib uptake. MicroRNAs able to induce hOCT1 mRNA decay were analyzed in paired samples of TCGA-CHOL (n = 9) and Copenhagen (n = 57) cohorts. Consistent up-regulation in tumor tissue was found for miR-141 and miR-330. High proportion of aberrant hOCT1 mRNA splicing in CCA was also seen. Lentiviral-mediated transduction of eCCA (EGI-1 and TFK-1) and iCCA (HuCCT1) cells with hOCT1 enhanced sorafenib uptake and cytotoxic effects. In chemically induced CCA in rats, reduced rOct1 expression was accompanied by impaired sorafenib uptake. In xenograft models of eCCA cells implanted in mouse liver, poor response to sorafenib was observed. However, tumor growth was markedly reduced by cotreatment with sorafenib and adenoviral vectors encoding hOCT1 under the control of the BIRC5 promoter, a gene highly up-regulated in CCA. Conclusion: The reason for impaired hOCT1-mediated sorafenib uptake by CCA is multifactorial. Gene therapy capable of selectively inducing hOCT1 in tumor cells can be considered a potentially useful chemosensitization strategy to improve the response of CCA to sorafenib

Second-line treatment in advanced gastric cancer : Data from the Spanish AGAMENON registry

Second-line treatments boost overall survival in advanced gastric cancer (AGC). However, there is a paucity of information as to patterns of use and the results achieved in actual clinical practice. The study population comprised patients with AGC in the AGAMENON registry who had received second-line. The objective was to describe the pattern of second-line therapies administered, progression-free survival following second-line (PFS-2), and post-progression survival since first-line (PPS). 2311 cases with 2066 progression events since first-line (89.3%) were recorded; 245 (10.6%) patients died during first-line treatment and 1326/2066 (64.1%) received a second-line. Median PFS-2 and PPS were 3.1 (95% CI, 2.9-3.3) and 5.8 months (5.5-6.3), respectively. The most widely used strategies were monoCT (56.9%), polyCT (15.0%), ramucirumab+CT (12.6%), platinum-reintroduction (8.3%), trastuzumab+CT (6.1%), and ramucirumab (1.1%). PFS-2/PPS medians gradually increased in monoCT, 2.6/5.1 months; polyCT 3.4/6.3 months; ramucirumab+CT, 4.1/6.5 months; platinum-reintroduction, 4.2/6.7 months, and for the HER2+ subgroup in particular, trastuzumab+CT, 5.2/11.7 months. Correlation between PFS since first-line and OS was moderate in the series as a whole (Kendall's τ = 0.613), lower in those subjects who received second-line (Kendall's τ = 0.539), especially with ramucirumab+CT (Kendall's τ = 0.413). This analysis reveals the diversity in second-line treatment for AGC, highlighting the effectiveness of paclitaxel-ramucirumab and, for a selected subgroup of patients, platinum reintroduction; both strategies endorsed by recent clinical guidelines

Multi-omics analyses reveal that HIV-1 alters CD4+ T cell immunometabolism to fuel virus replication

Individuals infected with human immunodeficiency virus type-1 (HIV-1) show metabolic alterations of CD4+ T cells through unclear mechanisms with undefined consequences. We analyzed the transcriptome of CD4+ T cells from patients with HIV-1 and revealed that the elevated oxidative phosphorylation (OXPHOS) pathway is associated with poor outcomes. Inhibition of OXPHOS by the US Food and Drug Administration–approved drug metformin, which targets mitochondrial respiratory chain complex-I, suppresses HIV-1 replication in human CD4+ T cells and humanized mice. In patients, HIV-1 peak viremia positively correlates with the expression of NLRX1, a mitochondrial innate immune receptor. Quantitative proteomics and metabolic analyses reveal that NLRX1 enhances OXPHOS and glycolysis during HIV-1-infection of CD4+ T cells to promote viral replication. At the mechanistic level, HIV infection induces the association of NLRX1 with the mitochondrial protein FASTKD5 to promote expression of mitochondrial respiratory complex components. This study uncovers the OXPHOS pathway in CD4+ T cells as a target for HIV-1 therapy