TP53 outperforms other androgen receptor biomarkers to predict abiraterone or enzalutamide outcome in metastatic castration-resistant prostate cancer

Purpose: To infer the prognostic value of simultaneous androgen receptor (AR) and TP53 profiling in liquid biopsies from patients with metastatic castration-resistant prostate cancer (mCRPC) starting a new line of AR signaling inhibitors (ARSi). Experimental Design: Between March 2014 and April 2017, we recruited patients with mCRPC (n = 168) prior to ARSi in a cohort study encompassing 10 European centers. Blood samples were collected for comprehensive profiling of Cell Search-enriched circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). Targeted CTC RNA sequencing (RNA-seq) allowed the detection of eight AR splice variants (ARV). Low-pass whole-genome and targeted gene-body sequencing of AR and TP53 was applied to identify amplifications, loss of heterozygosity, mutations, and structural rearrangements in ctDNA. Clinical or radiologic progression-free survival (PFS) was estimated by Kaplan-Meier analysis, and independent associations were determined using multivariable Cox regression models. Results: Overall, no single AR perturbation remained associated with adverse prognosis after multivariable analysis. Instead, tumor burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS. TP53 inactivation harbored independent prognostic value [HR 1.88; 95% confidence interval (CI), 1.18-3.00; P = 0.008], and outperformed ARV expression and detection of genomic AR alterations. Using Cox coefficient analysis of clinical parameters and TP53 status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs. 7.51 vs. 2.62 months; P < 0.0001), which was validated in an independent mCRPC cohort (n = 202) starting first-line ARSi (median, 14.3 vs. 6.39 vs. 2.23 months; P < 0.0001). Conclusions: In an all-comer cohort, tumor burden estimates and TP53 outperform any AR perturbation to infer prognosis. See related commentary by Rebello et al., p. 169

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis.

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.BACKGROUND: There are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited. METHODS: A combination of targeted and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients. RESULTS: ctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first-line metastatic castration-resistant prostate cancer therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%). Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (≥ 0.1 ctDNA fraction). Sequencing of non-repetitive intronic and exonic regions of PTEN, RB1, and TP53 detected biallelic inactivation in 47.5%, 20.3%, and 44.1% of samples with ≥ 0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays. CONCLUSIONS: ctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenges the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials.The Belgian Foundation Against Cancer (grant number C/2014/227); Kom op tegen Kanker (Stand up to Cancer), the Flemish Cancer Society (grant number 00000000116000000206); Royal College of Surgeons/Cancer Research UK (C19198/A1533); The Cancer Research Funds of Radiumhemmet, through the PCM program at KI (grant number 163012); The Erling-Persson family foundation (grant number 4-2689-2016); the Swedish Research Council (grant number K2010-70X-20430-04-3), and the Swedish Cancer Foundation (grant number 09-0677)

Continuous infusion of vancomycin in non-ICU patients : why, how and what's the benefit?

Therapeutic Drug Monitoring (TDM) of vancomycin is widely recommended yet its performance in routine practice is rarely assessed. In the first part of the PhD thesis we performed a combined observational and qualitative study in order to assess routine TDM performance and adherence to local hospital TDM guidelines for vancomycin and to evaluate the impact of continuous infusion on the quality of TDM services. Baseline: 4 months observational study (vanncomycin BID, 46 patients, 132 samples). Intervention: switch to continuous infusion [CI] with centralised drug preparation (1 year, 92 patients, 224 samples). Process indicators: (i) correct sample timing; (ii) implementation of TDM dosage readjustment recommendations; (iii) prescribed daily dose in accordance to hospital guidelines; (iv) proportion of serum levels values within the recommended ranges. Qualitative studies: focus groups and structured interviews with ward and laboratory personnel to identify difficulties and barriers in TDM performance at baseline and assess satisfaction/dissatisfaction with the intervention. TDM performance was poor at baseline (BID) with only 53% of peak and 66% of trough samples collected within 30 min from scheduled time, 13% of peak levels and 48% of trough levels within recommended therapeutic ranges [84% too low], 32% implementation of dosage re-adjustment recommendation, and 83% incorrect prescribed daily doses (average: 20% lower). Insufficient knowledge and training of HCPs, and organisational issues were the main reasons for poor adherence and perceived as critical barriers. Implementation of CI was associated with significant improvement (p 1 mg/L. Nephrotoxicity potentially related to vancomycin was observed in 10% of patients, but treatment had to be discontinued in only two of them.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 201

Schéma directeur de restauration des landes / habitat de dunes grises dans le Schuddebeurze

International audienceThe Schuddebeurze, a sub-recent decalcified dune complex on the Belgian coast, forms part of the Special Area of Conservation (SAC)“Dunes including IJzer estuary and Zwin”. It was mainly assigned as SAC for the presence of (degraded) acidified grey dunes (habitat type2130*) and a relic population of dune heath (2150*). The ponds contain a population of the Great Crested Newt (Triturus cristatus). As the abioticconditions are favorable for the restoration of these specific dune habitat types, the Flemish government investigates the feasibility of a naturerestoration project in the Schuddebeurze. Besides nature restoration to realise the conservation goals, attention will have to be paid to the culturalheritage elements of the First and Second World War on the site. Another challenge is that in more recent history, there have been extractionactivities for sand and/or clay in the Schuddebeurze, after which many of the pits were filled with waste. In this stage of the process, inventorystudies have been performed to investigate the feasibility of a nature restoration project and a preliminary masterplan has been developed.This plan needs refinement and discussion with the different administrations and the public.Schuddebeurze, sur le littoral belge, est un complexe de dunes décalcifiées lors des périodes subrécentes et a été incorporé dans lazone spéciale de conservation “Dunes, incluant l’estuaire de l’IJzer et le Zwin”. L’incorporation dans la zone spéciale de conservation reposesur la présence de dunes grises acidifiées (dégradées) (code de l’habitat 2130*) et de reliques de landes dunaires (2150*). Les maresabritent une population de Triton crêté (Triturus cristatus). Du fait des conditions abiotiques favorables pour la restauration d’habitats detype dunaires, le gouvernement flamand étudie la faisabilité d’un projet de restauration des habitats naturels à Schuddebeurze. En plusde la restauration du milieu naturel afin de réaliser les buts de conservation, une attention particulière devra être apportée au patrimoinelié à la première et la deuxième guerre mondiale présent sur le site. Autre challenge à relever, les puits formés dans un passé récent parl’extraction de sable et d’argile, dont un grand nombre a été remblayé avec des déchets. A ce stade de développement, des études ontété réalisées afin d’évaluer la faisabilité du projet de restauration naturelle et un plan global préliminaire a aussi été établi. Ce plan mériteencore d’être affiné, après consultation auprès des différentes administrations impliquées et auprès du large public

Abstracts of the ESCP 37th European Symposium on Clinical Pharmacy, Pharmaceutical Care Models, and Therapeutic Innovations. Dubrovnik, Croatia. October 21-24, 2008. PC-20 A national initiative to harmonize a registration form for clinical pharmacy interventions

Background and Objective Clinical pharmacists often have to evaluate and quantify their work. Each Belgian hospital uses a dif- ferent tool to register their clinical pharmacy activities. There is a need to harmonize the way in which clinical pharmacy interventions are notified in the country to facilitate the spread of this profession. The objective of this study was to develop a validated tool to register clinical pharmacy interventions in Belgium, in the French and Dutch languages. This tool should be as practical and as close to daily pharmacists’ work as possible. Design Development and validation of an intervention form. Content validity and interrater reliability were evaluated; evaluations were made by 45 hospital pharmacists, based on a list of 50 real interventions. Setting Forty-five Belgian hospital pharmacists, including French and Dutch speakers, having experience or interest in clinical pharmacy participated. Main Outcome Measures Calculation of interrater reliability using the kappa coefficient (j) for the categories that could be codified (reason of intervention and intervention). The form and the instructions for use were also assessed for content validity using a satisfaction questionnaire. Results A seven-part form (general information, drug(s), a space to describe the background and the intervention, reason for intervention, intervention, acceptation, qualitative, and economic impact) and detailed instructions for use were developed based on other forms already used in Belgium and on forms of the literature. Two suc- cessive validation tests were required to achieve j[0.60, which is the minimum validation value. The form and instructions for use were improved between the first and second test. After the second valida- tion test, j ‘‘reason of intervention’’ and j ‘‘intervention’’ were 0.65 and 0.80, respectively. All the participating pharmacists answered in the satisfaction questionnaire that they were pleased with the tool and ready to use it in their daily practice. Conclusions A new tool to register clinical pharmacy interventions in Belgium has been developed and validated. Reassessment and mod- ifications could be considered in the future based on users’ opinion. The documentation of the pharmacist’s advices, the interventions, and their acceptance will help to justify clinical pharmacists’ activities and to develop new clinical pharmacy services in our country

Correlation between free and total vancomycin serum concentrations in patients treated for Gram-positive infections

Routine therapeutic drug monitoring (TDM) reports only total vancomycin (VAN) concentrations, although protein binding varies and it is generally accepted that only free VAN is active. The aims of this study were to examine the correlation between free and total VAN concentrations in order to estimate whether free VAN levels can be predicted based on its total concentration. A high-performance liquid chromatography (HPLC) method was set up and validated (against routine laboratory immunoassays) for measurement of free [ultrafiltration (Centrifree((R))); cut-off 30kDa] and total [solid-phase extraction (Oasis((R)) MCX cartridge)] VAN in serum. Samples (n=65) from patients (n=15) treated by continuous infusion were analysed. There was a wide variation in free to total VAN ratios [range 12-100%; mean 63.6+/-25.8%, with 59 values falling outside the 95% confidence interval (57.3-69.9%); median 70.2%]. The correlation between free and total VAN was poor (R(2)=0.55). Artefacts such as pH variation of sera could be excluded. Both intrapatient and interpatient variabilities were large and no correlation could be made with patients' clinical conditions. Total VAN concentration is not predictive of free VAN concentration, suggesting that actual determination of free VAN might be recommended as an improved method of TDM

Stability and compatibility of vancomycin for administration by continuous infusion

BACKGROUND: Vancomycin is increasingly used by continuous infusion, but few specific data are available about stability under practical conditions of preparation and use, and compatibility with other intravenous drugs commonly used in the routine hospital setting. METHODS: Vancomycin stability [defined as recovery ≥ 93% of the original content (validated HPLC assay)] was examined throughout the whole process of centralized preparation, storage and use in the ward by infusion for up to 48 h, with allowances for deviations from recommended practice [exposure to high temperature; use of concentrated solutions (up to 83 g/L)]. Compatibility was assessed by mimicking co-administration in a single line via Y-shaped connectors with contact of 1 h at 25°C, followed by visual inspection (professional viewer), detection of particulate matter (particle analyser) and HPLC assay of vancomycin. RESULTS: Vancomycin was stable during the whole process and also during 72 h exposure of concentrated solutions at temperatures up to 37°C. Major incompatibilities were seen with β-lactams (temocillin, piperacillin/tazobactam, ceftazidime, imipenem, cefepime and flucloxacillin) and moxifloxacin, but not with ciprofloxacin, aminoglycosides and macrolides. Propofol, valproic acid, phenytoin, theophylline, methylprednisolone and furosemide were also incompatible, whereas ketamine, sufentanil, midazolam, morphine, piritramide, nicardipine, urapidil, dopamine, dobutamine and adrenaline were compatible. No effect or incompatibility with N-acetyl-cysteine or amino acid solutions was detected. CONCLUSIONS: Centralized preparation of vancomycin and its use by continuous infusion in wards is safe concerning stability, but careful attention must be paid to incompatibilities. Several drugs (including all β-lactams) require distinct intravenous lines or appropriate procedures to avoid undue contact