Pembrolizumab plus Olaparib in Patients with Metastatic Castration-resistant Prostate Cancer: Long-term Results from the Phase 1b/2 KEYNOTE-365 Cohort A Study

Metastatic castration-resistant prostate cancer; Olaparib; PembrolizumabCáncer de próstata metastásico resistente a la castración; Olaparib; PembrolizumabCàncer de pròstata metastàtic resistent a la castració; Olaparib; PembrolizumabBackground Pembrolizumab and olaparib have shown single-agent activity in patients with previously treated metastatic castration-resistant prostate cancer (mCRPC). Objective To evaluate the efficacy and safety of pembrolizumab plus olaparib in mCRPC. Design, setting, and participants Cohort A of the phase 1b/2 KEYNOTE-365 study enrolled patients with molecularly unselected, docetaxel-pretreated mCRPC whose disease progressed within 6 mo of screening. Intervention Pembrolizumab 200 mg intravenously every 3 wk plus olaparib 400-mg capsule or 300-mg tablet orally twice daily. Outcome measurements and statistical analysis The primary endpoints were safety, confirmed prostate-specific antigen (PSA) response rate, and objective response rate (ORR) as per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, by blinded independent central review. The secondary endpoints included radiographic progression-free survival (rPFS) and overall survival (OS). Results and limitations Of 104 enrolled patients, 102 were treated. The median age was 70 yr (interquartile range [IQR], 65–76), and 59 patients (58%) had measurable disease as per RECIST v1.1. The median time from the first dose to database cutoff was 24 mo (IQR, 22–47). The confirmed PSA response rate was 15%. The confirmed ORR was 8.5% (five partial responses) for patients with measurable disease. The median rPFS was 4.5 mo (95% confidence interval [CI], 4.0–6.5) and median OS was 14 mo (95% CI, 10.4–18.2). Clinical activity was consistent across the programmed death ligand 1 (PD-L1)-positive and homologous recombination repair mutation subgroups. Treatment-related adverse events (TRAEs) occurred in 93 patients (91%). Grade 3–5 TRAEs occurred in 49 patients (48%). Six deaths (5.9%) were due to adverse events; two (myocardial infarction and unknown cause) were attributed to treatment. Limitations of the study include the single-arm design. Conclusions Pembrolizumab plus olaparib had a safety profile consistent with the profiles of the individual agents and demonstrated antitumor activity in previously treated patients with molecularly unselected, docetaxel-pretreated mCRPC

Direct determination of free metal concentration by implementing stripping chronopotentiometry as second stage of AGNES

The electroanalytical technique Absence of Gradients and Nernstian Equilibrium Stripping (AGNES) has been extended by applying stripping chronopotentiometry (SCP) as the re-oxidation stage in the determination of the free concentration of Zn2+, Cd2+ and Pb2+. This new approach, called AGNES-SCP, has been implemented with screen-printed electrodes (SPE) and the standard Hanging Mercury Drop Electrode (HMDE). Clear advantages of this variant have been shown: (i) the easy resolution of the peaks of different metals present in mixtures and (ii) the sparing of blanks. A rigorous computation of the faradaic charge along the SCP stage takes into account the contribution of other oxidants, which can be efficiently measured at the end of the deposition stage of AGNES. The free Cd concentration determined in an oxalate solution at pH 6 with an HMDE as the working electrode agreed well with values obtained with a Cd Ion Selective Electrode. The free metal concentration measured using an SPE for the system Cd and nitrilotriacetic acid (NTA) at pH = 4.8 also conformed well with Visual MINTEQ results

Non-purged voltammetry explored with AGNES

The reduction of oxygen increases pH in the surroundings of an electrode. A theoretical model estimates the steady-state pH profile from the surface of the electrode up to the bulk solution. A very simple formula predicts that, in non-deareated solutions, for bulk pH-values between 4.0 and 10.0, the corresponding surface pH could be as high as 10.3, regardless of the thickness of the diffusion layer and composition of the sample (except if it has a buffering capacity). For bulk pH lower than 3.0 or higher than 10, pH increases are negligible. Less steep pH-profiles are obtained with buffers (such as MOPS 0.01 M or MES 0.01 M). The change in surface pH modifies the local speciation and hinders the standard interpretation of voltammetric responses. The electroanalytical technique Absence of Gradients and Nernstian Equilibrium Stripping (AGNES), implemented with Screen Printed Electrodes (SPE), provides experimental insights into this phenomenon. AGNES probes the free metal concentration at the electrode surface, from which the surface pH can be estimated for systems of known composition. These estimations agree with the theoretical model for the assayed systems. Additionally, the quantification of the bulk free Zn2+ and Cd2+ concentrations with specific modifications of AGNES for non-purged synthetic solutions is discussed. In general, more accurate determinations of the bulk free metal concentrations in non-purged solutions are expected: i) when the calibration is performed in a medium where the pH increase induces similar changes in the surface free metal concentration and in the sample solution and ii) when the system is more buffered.This work was financially supported by the Spanish Ministry of Education and Science (Projects CTQ2009-07831, CTM2009-14612 and CTM2012-39183), from the “Comissionat per a Universitats i Recerca del Departament d'Innovació, Universitats i Empresa de la Generalitat de Catalunya”

Accumulation of Mg to Diffusive Gradients in Thin Films (DGT) devices: Kinetic and thermodynamic effects of the ionic strength

Availability of magnesium is a matter of concern due to its role in many environmental and biological processes. Diffusive Gradients in Thin Films (DGT) devices can measure Mg availability in situ. This work shows that Mg accumulation in water largely increases when ionic strength (I) decreases. This phenomenon can be explained from (i) the increase of both the association equilibrium (K) and rate (ka,R) constants for the reaction between Mg cations and resin sites, and (ii) the growing contribution of the partitioning of Mg cations at the resin–gel interface, as I decreases. Two theoretical models that take into account electrical interactions among Mg cations, background electrolyte, and resin sites can successfully be used to determine ka,R and K at each I. Both models yield similar ka,R values, which fulfill an expression for the kinetic salt effect. For freshwater (with a typical salinity of 10 mM and circumneutral pH), the binding of Mg is so fast and strong that the simplest perfect-sink DGT expression can be helpful to predict (overestimation lower than 5%) the accumulation in solutions with Mg concentrations up to 1 mM whenever the deployment time is below 9 h. Perfect sink conditions can still be applied for longer times, in systems with either a lower I or a lower Mg concentration.Financial support from FEDER and the Spanish Ministry of Education and Science (Projects CTM2012-39183 and CTM2013-48967) is gratefully acknowledged

Free Zn2+ determination in natural freshwater of the Pyrenees: towards on-site measurements with AGNES

An on-site methodology has been developed for the direct determination of free Zn2+ with AGNES (Absence of Gradients and Nernstian Equilibrium Stripping) in freshwaters. This implementation includes: i) the use of screen printed electrodes, which provide good limits of detection and easy transportation and deployment; ii) no need for sample purging; iii) a calibration in a synthetic river solution that reproduces well the speciation changes of the natural samples and allows the oxygen interferences to be minimised; iv) the addition of a background electrolyte up to 0.01 mol L-1 in both the calibration and freshwater samples; v) chemical stripping chronopotentiometry as the quantification stage of AGNES. This procedure minimizes the effects of working at low ionic strength and in the presence of dissolved oxygen. In the laboratory, the methodology was checked with different natural samples taken from rivers Garonne, Gave de Cauterets and Gave de Pau in the Pyrenees. Results appeared in good agreement with theoretical estimations computed from Visual Minteq. On-site measurements were performed for the first time with AGNES in the Gave de Cauterets in Soulom (France) and the results were corroborated with purged measurements performed in the laboratory.English language editing by Holly Pearson is acknowledged. The authors acknowledge support for this research from the Communaut e d’Agglom eration de Pau Pyr en ees (CDAPP), from the Spanish Ministerio de Ciencia e Innovacio´n (project numbers CTM2012–39183 and CTM2013– 48967), from the European Community EFA15/08 (PyrMet) and from the Comissionat d’Universitats i Recerca de la Generalitat de Catalunya (project number 2014SGR1132)

Prevalence of anaemia and its clinical management in patients with stages 3-5 chronic kidney disease not on dialysis in Catalonia: MICENAS I study

Introducción: La anemia es una complicación frecuente de la enfermedad renal crónica (ERC). El objetivo de este estudio fue conocer la prevalencia de anemia en pacientes con ERC estadios 3-5 no en diálisis atendidos en consultas externas (CCEE) de Nefrología en Cataluña y su manejo clínico. Metodología: Estudio epidemiológico, de cohorte transversal, multicéntrico, en condiciones de práctica clínica habitual. Recogida de datos mediante un e-CRD que incluía datos de filiación y aquellos relacionados con la anemia (hemoglobina, estatus férrico, tratamiento con agentes estimuladores de la eritropoyesis [AEE] y con otros coadyuvantes). Se definió anemia como unos niveles de hemoglobina < 13,5 g/dl en varones o < 12 g/dl en mujeres o pacientes que recibieran tratamiento con AEE. Resultados: Se incluyeron 504 pacientes (56,4 % varones, edad media de 67,8 ± 15,5 años): 61,5 % presentaban ERC estadio 3, 30,2 % estadio 4 y 8,3 % estadio 5. Las principales causas de ERC fueron la vascular y la nefropatía diabética. La prevalencia de anemia fue del 58,5 % (n = 295); sin embargo, solo un 14,9 % de los pacientes tenían niveles de hemoglobina < 11 g/dl. Los niveles medios de hemoglobina disminuían y el tratamiento con AEE era más frecuente a medida que progresaba la ERC, pero no se observaron diferencias significativas respecto a la prescripción de hierro, según estadios. Los AEE e intervalos más frecuentemente prescritos fueron darbepoetina alfa con una dosis mediana de 40 μg/bisemanal, seguida por C.E.R.A., con una dosis mediana de 75 μg/mensual y epoetina beta con una dosis mediana de 5000 UI/semanal. De los pacientes con anemia (n = 295), un 36,3 % (n = 107) presentaban ferropenia y de ellos solo un 53,3 % recibía tratamiento con suplementos de hierro. Conclusiones: Este estudio demuestra la alta prevalencia de anemia, la cual aumenta a medida que progresa la enfermedad, así como el buen control de la misma en la población de pacientes con ERC atendidos en CCEE de Nefrología en Cataluña. Este control se consigue con dosis moderadas de AEE y prescripción de suplementos de hierro en más del 50 % de los pacientes anémicos

Risk factors for non-diabetic renal disease in diabetic patients

Background. Diabetic patients with kidney disease have a high prevalence of non-diabetic renal disease (NDRD). Renal and patient survival regarding the diagnosis of diabetic nephropathy (DN) or NDRD have not been widely studied. The aim of our study is to evaluate the prevalence of NDRD in patients with diabetes and to determine the capacity of clinical and analytical data in the prediction of NDRD. In addition, we will study renal and patient prognosis according to the renal biopsy findings in patients with diabetes. Methods. Retrospective multicentre observational study of renal biopsies performed in patients with diabetes from 2002 to 2014. Results. In total, 832 patients were included: 621 men (74.6%), mean age of 61.7 6 12.8 years, creatinine was 2.8 6 2.2 mg/dL and proteinuria 2.7 (interquartile range: 1.2–5.4) g/24 h. About 39.5% (n ¼ 329) of patients had DN, 49.6% (n ¼ 413) NDRD and 10.8% (n ¼ 90) mixed forms. The most frequent NDRD was nephroangiosclerosis (NAS) (n ¼ 87, 9.3%). In the multivariate logistic regression analysis, older age [odds ratio (OR) ¼ 1.03, 95% CI: 1.02–1.05, P < 0.001], microhaematuria (OR ¼ 1.51, 95% CI: 1.03–2.21, P ¼ 0.033) and absence of diabetic retinopathy (DR) (OR ¼ 0.28, 95% CI: 0.19–0.42, P < 0.001) were independently associated with NDRD. Kaplan–Meier analysis showed that patients with DN or mixed forms presented worse renal prognosis than NDRD (P < 0.001) and higher mortality (P ¼ 0.029). In multivariate Cox analyses, older age (P < 0.001), higher serum creatinine (P < 0.001), higher proteinuria (P < 0.001), DR (P ¼ 0.007) and DN (P < 0.001) were independent risk factors for renal replacement therapy. In addition, older age (P < 0.001), peripheral vascular disease (P ¼ 0.002), higher creatinine (P ¼ 0.01) and DN (P ¼ 0.015) were independent risk factors for mortality. Conclusions. The most frequent cause of NDRD is NAS. Elderly patients with microhaematuria and the absence of DR are the ones at risk for NDRD. Patients with DN presented worse renal prognosis and higher mortality than those with NDRD. These results suggest that in some patients with diabetes, kidney biopsy may be useful for an accurate renal diagnosis and subsequently treatment and prognosis