Patients with advanced urothelial carcinoma have poor overall survival after platinum-containing chemotherapy and programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor ...treatment.
We conducted a global, open-label, phase 3 trial of enfortumab vedotin for the treatment of patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-containing chemotherapy and had had disease progression during or after treatment with a PD-1 or PD-L1 inhibitor. Patients were randomly assigned in a 1:1 ratio to receive enfortumab vedotin (at a dose of 1.25 mg per kilogram of body weight on days 1, 8, and 15 of a 28-day cycle) or investigator-chosen chemotherapy (standard docetaxel, paclitaxel, or vinflunine), administered on day 1 of a 21-day cycle. The primary end point was overall survival.
A total of 608 patients underwent randomization; 301 were assigned to receive enfortumab vedotin and 307 to receive chemotherapy. As of July 15, 2020, a total of 301 deaths had occurred (134 in the enfortumab vedotin group and 167 in the chemotherapy group). At the prespecified interim analysis, the median follow-up was 11.1 months. Overall survival was longer in the enfortumab vedotin group than in the chemotherapy group (median overall survival, 12.88 vs. 8.97 months; hazard ratio for death, 0.70; 95% confidence interval CI, 0.56 to 0.89; P = 0.001). Progression-free survival was also longer in the enfortumab vedotin group than in the chemotherapy group (median progression-free survival, 5.55 vs. 3.71 months; hazard ratio for progression or death, 0.62; 95% CI, 0.51 to 0.75; P<0.001). The incidence of treatment-related adverse events was similar in the two groups (93.9% in the enfortumab vedotin group and 91.8% in the chemotherapy group); the incidence of events of grade 3 or higher was also similar in the two groups (51.4% and 49.8%, respectively).
Enfortumab vedotin significantly prolonged survival as compared with standard chemotherapy in patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-based treatment and a PD-1 or PD-L1 inhibitor. (Funded by Astellas Pharma US and Seagen; EV-301 ClinicalTrials.gov number, NCT03474107.).
MXene solid solutions have attracted intense attention due to their various properties that are potentially useful for emerging technological applications. In particular, magnetic 2D MXenes have been ...obtained typically using magnetic Cr, Mn, and V cations. Here, using first-principles calculations, we show that magnetic behavior comparable to that of the Cr-, Mn-, and V-containing MXenes can be obtained in a MXene solid solution (Nb1–x Ti x )4C3 created from two non-magnetic end-members. The magnetization emerges due to the energetically driven segregation of Ti atoms on the solid solution surface that creates localized unpaired 3d electrons. The magnetic behavior of the solid solution is preserved upon the functionalization of the MXene surface by F and OH and is removed by functionalization with O. We show that variations in magnetism are primarily caused by differences in the locations of the titanium atoms. These findings suggest another approach for the design and tuning of magnetism in the 2D MXene family of materials.
A nuanced introduction to the schools of the 12th century, insisting on the fertile confluence between ancient knowledge and new techniques and on the interaction between masters and pupils.
Three cobalt(III) complexes of regioisomeric trans-A2B-corroles were designed and efficiently synthesized. The corroles were adsorbed on smooth glassy carbon (GC) and black pearls 2000 (BP2000), ...high-surface-area carbon. Albeit spatially separated from the cobalt reaction center, the position of COOH group has a profound influence on the oxygen reduction reaction electrocatalytic reactivity when on GC, whereas on BP2000, a significant increase in selectivity toward the 4-electron reduction was observed in an alkaline environment. This is attributed to the wetting properties of the hydrophobic pores of BP2000, which considerably lower the dielectric constant in the pore water environment, stabilize the charged OOH– intermediate, and favor the 4-electron reduction pathway with the cobalt-bis-pentafluorophenyl (phenyl-para-carboxylic acid), when compared to analogous corroles with the COOH group at the ortho- and meta-positions.
Atezolizumab is an anti–PD-L1 immune checkpoint inhibitor recommended for the treatment of locally advanced or metastatic urothelial carcinoma (mUC) after prior platinum-containing chemotherapy, ...regardless of PD-L1 status, among other treatment settings. We conducted a long-term follow-up to the exploratory analysis of overall survival (OS) and safety for the IMvigor211 intent-to-treat (ITT) population. Patients with mUC and disease progression during or following platinum-based chemotherapy were randomised 1:1 to receive atezolizumab 1200 mg or chemotherapy (vinflunine 320 mg/m2, paclitaxel 175 mg/m2, or docetaxel 75 mg/m2 according to investigator choice) intravenously every 3 wk. Although the primary analysis did not demonstrate statistically significant longer OS for patients receiving atezolizumab versus chemotherapy, updated OS showed long-term durable remission. With a median of 33 mo of follow-up, the 24-mo OS rate was 23% with atezolizumab and 13% with chemotherapy. Safety findings were consistent with the primary analysis, with no new signals detected. Chemotherapy-treated patients experienced more grade 3/4 treatment-related adverse events (AEs; 43% vs 22%) and more AEs leading to treatment discontinuation (18% vs 9%). Atezolizumab-treated patients experienced more AEs of special interest (35% vs 20%), which tended to be grade 1–2. Our findings support the use of atezolizumab in platinum-treated patients with mUC regardless of PD-L1 status.
We report follow-up results from a study of an immunotherapy treatment, atezolizumab, in patients with bladder cancer who had already received platinum-containing chemotherapy. This analysis compared the effectiveness of atezolizumab with chemotherapy over 2.5 years after starting treatment. The results show that patients who received atezolizumab lived longer and had manageable side effects compared with patients who received chemotherapy. This trial is registered at ClinicalTrials.gov as NCT02302807.
Atezolizumab (an anti–PD-L1 immune checkpoint inhibitor) led to numerically better long-term overall survival than chemotherapy among patients with locally advanced or metastatic urothelial carcinoma after prior platinum-based chemotherapy. Adverse events over 2–3 yr were consistent with the known atezolizumab safety profile.
Immune checkpoint inhibitors (ICIs) are approved for first-line (cisplatin unfit, PD-L1+) and platinum-refractory urothelial carcinoma (UC). Still, most patients experience progressive disease (PD) ...as the best response. Although higher response rates to subsequent systemic treatment (SST) have been described, post-PD outcome data are scarce.
To examine the outcome of UC patients who received SST and no SST after progressing to ICIs.
A retrospective analysis of UC patients progressing to frontline or later-line anti–PD-1/PD-L1 therapy in 10 European institutions was conducted between March 2013 and September 2017.
Post-PD management as per standard practice.
Overall survival (OS) was analyzed with a Kaplan-Meier model. Cox regression was used for multivariate analysis (MV). Impact of SST on OS was examined with a time-varying covariate model.
A total of 270 UC patients with PD to ICIs (69 frontline, 201 later line) were analyzed. Of the patients, 57% of frontline-ICI-PD and 34% of later-line-ICI-PD patients received SST, and SST had an impact on OS in MV (frontline: hazard ratio HR 0.22, 95% confidence interval CI 0.10–0.51, p < 0.001; later line: HR 0.22, 95% CI 0.13–0.36, p < 0.001). In the frontline-ICI-PD group, median OS with and without SST was 6.8 mo (95% CI 5.0–8.6) and 1.9 mo (95% CI 0.9–3.0), respectively. High disease burden (three or more metastatic sites: HR 2.49, p = 0.03; simultaneous liver/bone metastases: HR 3.93, p = 0.03) predicted worse survival. In later-line-ICI-PD group, response to ICIs (HR 0.37, p = 0.03), longer exposure to ICIs (HR 0.89, p = 0.002), and bone metastasis (HR 2.42, p < 0.001) predicted survival. The retrospective nature of this study and a lack of certain parameters limit the interpretation of our analysis.
Patients progressing to frontline ICIs are at risk of early death, excluding them from experiencing potential benefit from chemotherapy
Our analysis suggests that outcomes after failing immunotherapy are poor, particularly in UC patients who received no prior chemotherapy.
Urothelial cancer patients failing frontline immunotherapy are at risk of early death, excluding them from experiencing potential benefit from chemotherapy. This suggests that frontline immunotherapy should be restricted to patients with low risk of clinical deterioration.
This article presents a modelling approach to predict the low-frequency sound generated by entropy fluctuations interacting with isolated aerofoils. A model of the acoustic field is obtained based on ...a linearisation of the compressible Euler equations about a steady, potential, compressible mean flow. Mean flow variations of velocity and density are accounted for in the source term, but are neglected in the sound propagation. Using a Lorentz-type transformation, the problem is reduced to solving a Helmholtz equation. This equation is recast in integral form and a solution is obtained using a compact Green's function method. This approach places no restrictions on the entropy wavelength, while assuming that the acoustic wavelength is large compared to the profile chord and spacing. The source term is further simplified by assuming that the steady flow is a small perturbation to a uniform flow. The model is illustrated using a symmetric aerofoil and its performance is assessed against numerical simulations of the compressible Euler equations. Good agreement is found for all the frequencies of validity of the theory and for all the range of subsonic Mach numbers. The solution for a symmetric aerofoil interacting with plane entropy waves corresponds to the combination of a dipole along the horizontal axis and a monopole. The dipole originates from the unsteady drag experienced by the aerofoil owing to the fluctuations of density and the monopole from the strong local acceleration of the flow at the leading edge. The monopole term becomes negligible for low Mach numbers.
Quantum metrology enables some of the most precise measurements. In the life sciences, diamond-based quantum sensing has led to a new class of biophysical sensors and diagnostic devices that are ...being investigated as a platform for cancer screening and ultrasensitive immunoassays. However, a broader application in the life sciences based on nanoscale NMR spectroscopy has been hampered by the need to interface highly sensitive quantum bit (qubit) sensors with their biological targets. Here, we demonstrate an approach that combines quantum engineering with single-molecule biophysics to immobilize individual proteins and DNA molecules on the surface of a bulk diamond crystal that hosts coherent nitrogen vacancy qubit sensors. Our thin (sub-5 nm) functionalization architecture provides precise control over the biomolecule adsorption density and results in near-surface qubit coherence approaching 100 μs. The developed architecture remains chemically stable under physiological conditions for over 5 d, making our technique compatible with most biophysical and biomedical applications.
One of the most important sources of systematic uncertainties in the evaluation of measured cross sections is the absolute normalization of every dataset, which were often performed by measuring ...simultaneously the reference cross-section of the standard isotope. In other experiments the shape of the cross-section spectrum is normalized using as reference the integral value in a certain energy interval taken from an evaluated library. The choice of the energy interval used as reference has been often left up to the experimentalist criteria, leading to inconsistent normalizations and hardly assessable uncertainties. In this work the experimental datasets of the (n,f) cross section of many actinides are reviewed looking for the best suited energy interval to be recommended for renormalization purposes. Using standard integration intervals, wide enough to get very low statistical uncertainties, should improve the normalization of every experimental dataset, reducing so the associated total uncertainty when making the evaluation. A common integration range from 8 to 10 MeV is proposed for the whole set of actinides needed in fission applications. This energy range, which falls between the second and the third fission-chance thresholds, is characterized by a flat behaviour of the fission cross sections.
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