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INTRODUCTION: In 2022, nivolumab was granted marketing authorization for adjuvant treatment in patients at high risk of recurrence following surgery for localized invasive muscle urothelial carcinoma, who express PD-L1 on the operative specimen. We aimed to investigate its real-world utilization. MATERIALS AND METHODS: Our bi-centric real-world study, conducted at Foch Hospital and Georges Pompidou European Hospital between July 2022 and January 2024, included patients who underwent surgery for urothelial carcinoma or were referred for adjuvant nivolumab treatment at these centers. RESULTS: A total of 200 patients underwent surgery during the study period, of whom 70 met the high-risk criteria, with 46% of these patients not receiving adjuvant treatment due to ineligibility. Our survival outcomes among patients treated by nivolumab are consistent with the results of the CheckMate 274 study2 (Bajorin DF, N Engl J Med. 2021). Our study population was older and frailer than that of the study cohort, with a mean age of 69 years. Significant PD-L1 expression was observed in 66% of the tested patients. The median disease-free survival was 11.34 months in patients who received neoadjuvant chemotherapy followed by surgery and adjuvant nivolumab. Nivolumab was generally well-tolerated, but 25% of patients discontinued it due to toxicity. Our initial data on treatments for recurrence after adjuvant nivolumab highlighted the effectiveness of conventional chemotherapy (cisplatin or carboplatin combined with gemcitabine) and targeted chemotherapy (enfortumab vedotin). CONCLUSION: Our real-world data align with existing literature regarding adjuvant nivolumab in localized invasive muscle urothelial carcinoma.
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Unilateral spatial neglect (USN) is a highly prevalent neuropsychological syndrome. However, its assessment in clinical practice, mainly based on paper-and-pencil tests, encounters limits as only near space, called peripersonal, is assessed. However, USN is a multicomponent syndrome that can also affect far space, called extrapersonal. This space is not assessed in current clinical assessment although it can be more impacted than peripersonal space. Immersive virtual reality (VR) allows developing tasks in far space to assess this heterogeneity. This study aimed to test the feasibility and the relevance of an immersive VR task to assess far space. A cancellation task, the Bells test, was used in its original paper-and-pencil version and was also adapted into a far immersive VR version. Ten patients with left USN and sixteen age-matched healthy participants were included. A single-case method was performed to investigate the performance of each patient. Although five patients showed very similar results between both versions, the five others exhibited a dissociation with a more severe impairment in the VR version. Three of these five patients significantly differed from the healthy participants only on the VR version. As USN in far space is not brought to light by paper-and-pencil tests, immersive VR appears as a promising tool to detect USN affecting this space.
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Most cities face the problem of an aging infrastructure in need of extensive and ongoing repair, renovation or replacement. Since the 1980s, CCTV has been the industry standard for sewer system inspection and the main source of information for structural performance evaluation. Due to low inspection rates and the lack of information about sewer condition, deterioration models have been developed to simulate the condition of non-inspected sewers and assess the influence of several rehabilitation scenarios. This paper presents an innovative modelling tool for long-term sewer rehabilitation planning based on the integration of a deterioration and a rehabilitation model. The tool is demonstrated in full scale using CCTV and sewer data of the city of Sofia, in Bulgaria. Results provide tangible proofs of investment needs for sewer rehabilitation and support the utility in the negotiation of budgets with the municipality. Since age is one key variable for deterioration modelling, a new method is proposed to estimate missing construction years in the utility database with a prediction error of less than 7 years.
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Modelos Teóricos , Aguas del Alcantarillado , CiudadesRESUMEN
We report the impact of the ternary solution phase behaviour on the film morphology and crystallization of a model polymer:fullerene system. We employ UV-Vis absorption spectroscopy, combined with sequential filtration and dilution, to establish the phase diagram for regio-random poly(3-hexylthiophene-2,5-diyl) and phenyl-C61-butyric acid methyl ester (PCBM) in chlorobenzene. Films are systematically cast from one- and two-phase regions decoupling homogeneous and heterogenous nucleation, and the role of pre-formed aggregates from solutions. Increasing annealing temperature from 120 to 200 °C reveals a highly non-monotonic nucleation profile with a maximum at 170 °C, while the crystal growth rate increases monotonically. UV ozonolysis is employed to vary substrate energy, and found to increase nucleation rate and to promote a binary crystallization process. As previously found, exposure to light, under an inert atmosphere, effectively suppresses homogeneous nucleation; however, it has a considerably smaller effect on heterogeneous nucleation, either from solution aggregates or substrate-driven. Our results establish a quantitative link between solution thermodynamics, crystallization and provide insight into morphological design based on processing parameters in a proxy organic photovoltaic system.
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Oestrogen receptor negative (ER(-)) invasive ductal carcinoma (IDC) represents a significant clinical challenge and therefore prompts the discovery of novel biomarkers. Transient receptor potential melastatin 7 (TRPM7), a channel protein that also contains a regulatory kinase domain, is overexpressed in IDC and regulates migration. However, the molecular mechanism remains poorly defined. Here, we examined whether TRPM7 regulates migration by its channel function or by its kinase domain. A Magnesium Inhibited Cation current was recorded in two ER(-) highly metastatic breast cancer cell lines. Down-regulation of TRPM7 neither affected Ca(2+)-, nor Mg(2+)-homoeostasis but significantly reduced cell migration via a Ca(2+)-independent pathway. Notably, the overexpression of the truncated kinase domain form of TRPM7 decreased cell migration, while the overexpression of the wild-type form strongly increased it. Concomitantly, TRPM7 silencing reduced the myosin IIA heavy chain phosphorylation. Furthermore, we found higher TRPM7 expression in ER(-) IDC tissues and lymph nodes than in the non-invasive tumoural samples. In conclusion, TRPM7 plays a critical role in breast cancer cell migration through its kinase domain, and our data support the consideration of using TRPM7 as a novel biomarker and a potential therapeutic target in the treatment of human ER(-) IDC.
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Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Movimiento Celular/genética , Canales Catiónicos TRPM/fisiología , Calcio/metabolismo , Movimiento Celular/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células MCF-7 , Metástasis de la Neoplasia , Fosfotransferasas/química , Fosfotransferasas/fisiología , Estructura Terciaria de Proteína/fisiología , ARN Interferente Pequeño/farmacología , Receptores de Estrógenos/metabolismo , Canales Catiónicos TRPM/antagonistas & inhibidores , Canales Catiónicos TRPM/química , Células Tumorales CultivadasRESUMEN
BACKGROUND: Cross-clamping of the aorta during abdominal aortic aneurysm surgery induces muscle ischaemia with resultant morbidity. This study tested whether ischaemic postconditioning would decrease mitochondrial dysfunction in skeletal muscle by reducing oxidative stress. METHODS: Three groups (9 rats each) underwent surgery, including a control group without ischaemia and an ischaemia-reperfusion group that had 3 h ischaemia induced by aortic clamping and collateral vessel ligation, followed by 2 h of reperfusion. The third group had ischaemia for 3 h then underwent postconditioning comprising three short intervals of ischaemia-reperfusion at the onset of reperfusion. Activity of complexes I, II, III and IV of the mitochondrial respiratory chain was monitored in gastrocnemius muscle, along with oxidative stress measured by dihydroethidium (DHE) staining and antioxidant defence determined by measurement of glutathione levels. RESULTS: Ischaemia-reperfusion alone caused a significant reduction in maximal oxidative capacity (-31.8 per cent; P = 0.002), activity of complexes II, III and IV (-34.5 per cent; P = 0.007) and complex IV activity (-30.6 per cent; P = 0.039). It also increased reactive oxygen species (DHE staining increased to 223.1 per cent of control value; P = 0.027) and reduced antioxidant defence (glutathione level -28.6 per cent; P = 0.039). Postconditioning counteracted these deleterious effects by increasing mitochondrial complex I, II, III and IV activities, restoring muscle DHE staining and preserving glutathione content. CONCLUSION: Ischaemic postconditioning protects skeletal muscle mitochondria against ischaemia-reperfusion injury by reducing oxidative stress and preserving antioxidant defence in an experimental model. Mitochondrial protection to reduce reperfusion injury in clinical vascular surgery may be warranted.