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Variation of SIP in the overall ICI cohort and in progressing and non-progressing patients (A). Variation of immunosenescence markers (CD28 absence, CD57 expression, KLRG1 expression) on CD4 and CD8+ T-cells and variation of circulating TEMRA, naïve or TC1 CD8+ T-cells in the overall ICI cohort and in progressing and non-progressing patients (B)

Supplementary Methods

Patients characteristics in ICI discovery and validation cohorts

Purpose:CD28, CD57, and KLRG1 have been previously identified as markers of T-cell immunosenescence. The impact of immunosenescence on anti-PD(L)-1 (ICI) or platinum-based chemotherapy (PCT) in patients with advanced non–small cell lung cancer (aNSCLC) is unknown.Experimental Design:The percentage of CD28−, CD57+, KLRG1+ among CD8+ T cells [senescent immune phenotype (SIP)] was assessed by flow cytometry on blood from patients with aNSCLC before single-agent ICI (discovery cohort). A SIP cut-off was identified by log-rank maximization method and patients with aNSCLC treated with ICI (validation cohort) or PCT were classified accordingly. Proliferation and functional properties of SIP+ CD8+ T cells were assessed in vitro.Results:In the ICI discovery cohort (N = 37), SIP cut-off was 39.5%, 27% of patients were SIP+. In the ICI validation cohort (N = 46), SIP+ status was found in 28% of patients and significantly correlated with worse objective response rate (ORR; 0% vs. 30%, P = 0.04), median progression-free survival (PFS) [1.8 (95% confidence interval (CI), 1.3-NR) vs. 6.4 (95% CI, 2–19) months, P = 0.009] and median overall survival, OS [2.8 (95% CI, 2.0-NR) vs. 20.8 (95% CI, 6.0-NR) months, P = 0.02]. SIP+ status was significantly associated with circulating specific immunephenotypes, in vitro lower CD8+ T cells proliferation, lower IL2 and higher TNFα and IFNγ production. In the ICI-pooled population (N = 83), SIP+ status did not correlate with any clinical characteristics and it was associated with significantly worse ORR, PFS, and OS. In PCT cohort (N = 61), 11% of patients were SIP+. SIP status did not correlate with outcomes upon PCT.Conclusions:Circulating T-cell immunosenescence is observed in up to 28% of patients with aNSCLC and correlates with lack of benefit from ICI but not from PCT.See related commentary by Salas-Benito et al., p. 374

Purpose: CD28, CD57, and KLRG1 have been previously identified as markers of T-cell immunosenescence. The impact of immunosenescence on anti-PD(L)-1 (ICI) or platinum-based chemotherapy (PCT) in patients with advanced non–small cell lung cancer (aNSCLC) is unknown. Experimental Design: The percentage of CD28−, CD57+, KLRG1+ among CD8+ T cells [senescent immune phenotype (SIP)] was assessed by flow cytometry on blood from patients with aNSCLC before single-agent ICI (discovery cohort). A SIP cut-off was identified by log-rank maximization method and patients with aNSCLC treated with ICI (validation cohort) or PCT were classified accordingly. Proliferation and functional properties of SIP+ CD8+ T cells were assessed in vitro. Results: In the ICI discovery cohort (N = 37), SIP cut-off was 39.5%, 27% of patients were SIP+. In the ICI validation cohort (N = 46), SIP+ status was found in 28% of patients and significantly correlated with worse objective response rate (ORR; 0% vs. 30%, P = 0.04), median progression-free survival (PFS) [1.8 (95% confidence interval (CI), 1.3-NR) vs. 6.4 (95% CI, 2–19) months, P = 0.009] and median overall survival, OS [2.8 (95% CI, 2.0-NR) vs. 20.8 (95% CI, 6.0-NR) months, P = 0.02]. SIP+ status was significantly associated with circulating specific immunephenotypes, in vitro lower CD8+ T cells proliferation, lower IL2 and higher TNFα and IFNγ production. In the ICI-pooled population (N = 83), SIP+ status did not correlate with any clinical characteristics and it was associated with significantly worse ORR, PFS, and OS. In PCT cohort (N = 61), 11% of patients were SIP+. SIP status did not correlate with outcomes upon PCT. Conclusions: Circulating T-cell immunosenescence is observed in up to 28% of patients with aNSCLC and correlates with lack of benefit from ICI but not from PCT. See related commentary by Salas-Benito et al., p. 374

Immune checkpoint inhibitors are monoclonal antibodies (mAbs) directed against negative immunologic regulators that are used to restore the immune response against cancer. Approved drugs include anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), anti-programmed cell death 1 (PD-1) and anti-programmed cell death-ligand 1 (PD-L1) antibodies exhibiting pharmacokinetic (PK) characteristics typical of mAbs. Most factors such as age, sex, ethnicity, tumour burden, performance status and immunogenicity, but not body weight, do not seem to affect drug clearance clinically. However, an exposure-response relation has been described for both the efficacy and toxicity of anti-CTLA-4 and anti-PD-1 agents. The change in clearance over time is associated with overall response at least for nivolumab and pembrolizumab. Few PK/pharmacodynamic (PD) data are available for anti-PD-L1 mAbs, but time-varying clearance has been described for these drugs, and the high immunogenicity rate observed with atezolizumab may affect PK parameters and should be further studied. These data suggest the need for additional PK/PD studies. In this review, we summarise studies of the PKs of immune checkpoint inhibitors, exploring possible interactions with PD considerations.

BackgroundProgrammed cell death protein-1 (PD-1) expression has been associated with activation and exhaustion of both the CD4 and CD8 populations in advanced non-small cell lung cancer (aNSCLC). Nevertheless, the impact of the balance between circulating CD8+PD-1+ and CD4+PD-1+ in patients treated with immune checkpoint blockers (ICB) is unknown.MethodsThe CD8+PD-1+ to CD4+PD-1+ ratio (PD-1-Expressing Ratio on Lymphocytes in a Systemic blood sample, or ‘PERLS’) was determined by cytometry in fresh whole blood from patients with aNSCLC before treatment with single-agent ICB targeting PD-1 or programmed cell death-ligand 1 (PD-L1 (discovery cohort). A PERLS cut-off was identified by log-rank maximization. Patients treated with ICB (validation cohort) or polychemotherapy (control cohort) were classified as PERLS+/− (above/below cut-off). Circulating immune cell phenotype and function were correlated with PERLS. A composite score (good, intermediate and poor) was determined using the combination of PERLS and senescent immune phenotype as previously described in aNSCLC.ResultsIn the discovery cohort (N=75), the PERLS cut-off was 1.91, and 11% of patients were PERLS+. PERLS + correlated significantly with median progression-free survival (PFS) of 9.63 months (95% CI 7.82 to not reached (NR)) versus 2.69 months (95% CI 1.81 to 5.52; p=0.03). In an independent validation cohort (N=36), median PFS was NR (95% CI 7.9 to NR) versus 2.00 months (95% CI 1.3 to 4.5; p=0.04) for PERLS + and PERLS−, respectively; overall survival (OS) followed a similar but non-significant trend. In the pooled cohort (N=111), PERLS + correlated significantly with PFS and OS. PERLS did not correlate with outcome in the polychemotherapy cohort. PERLS did not correlate with clinical characteristics but was significantly associated with baseline circulating naïve CD4+ T cells and the increase of memory T cells post-ICB treatment. Accumulation of memory T cells during treatment was linked to CD4+ T cell polyfunctionality. The composite score was evaluated in the pooled cohort (N=68). The median OS for good, intermediate and poor composite scores was NR (95% CI NR to NR), 8.54 months (95% CI 4.96 to NR) and 2.42 months (95% CI 1.97 to 15.5; p=0.001), respectively. The median PFS was 12.60 months (95% CI 9.63 to NR), 2.58 months (95% CI 1.74 to 7.29) and 1.76 months (95% CI 1.31 to 4.57; pConclusionsElevated PERLS, determined from a blood sample before immunotherapy, was correlated with benefit from PD-(L)1 blockers in aNSCLC.

International audience; No abstract available

Programmed cell death protein-1 (PD-1) expression has been associated with activation and exhaustion of both the CD4 and CD8 populations in advanced non-small cell lung cancer (aNSCLC). Nevertheless, the impact of the balance between circulating CD8The CD8In the discovery cohort (N=75), the PERLS cut-off was 1.91, and 11% of patients were PERLS+. PERLS + correlated significantly with median progression-free survival (PFS) of 9.63 months (95% CI 7.82 to not reached (NR)) versus 2.69 months (95% CI 1.81 to 5.52; p=0.03). In an independent validation cohort (N=36), median PFS was NR (95% CI 7.9 to NR) versus 2.00 months (95% CI 1.3 to 4.5; p=0.04) for PERLS + and PERLS-, respectively; overall survival (OS) followed a similar but non-significant trend. In the pooled cohort (N=111), PERLS + correlated significantly with PFS and OS. PERLS did not correlate with outcome in the polychemotherapy cohort. PERLS did not correlate with clinical characteristics but was significantly associated with baseline circulating naïve CD4Elevated PERLS, determined from a blood sample before immunotherapy, was correlated with benefit from PD-(L)1 blockers in aNSCLC.

724 Background: The NIVOREN GETUG-AFU 26 study launched a translational research program to quantify baseline circulating soluble factors levels and correlate them with outcomes and irAEs in mRCC pts treated with nivolumab. We previously identified (training-set = 80 pts, validation-set= 233 pts) several soluble factors associated with overall survival (IL-6, IL-8, VEGF, BAFF, and CXCL13) (Carril-Ajuria et al. ASCO. 2022). Our aim was to evaluate the association between baseline levels of circulating soluble factors and the presence of all grade and severe irAEs. Methods: 720 patients treated with nivolumab within the NIVOREN study and with available safety data were included in the study. The association between baseline levels of seven different circulating soluble factors (VEGF, VCAM-1, IL-6, IL-7, IL-8, BAFF, CXCL13) and the development of all grade and severe irAEs was evaluated in those pts who had previously undergone soluble factors quantification within the translational program. The association between other systemic inflammatory markers (the lung immune prognostic index (LIPI), LDH and the derived neutrophil to lymphocyte ratio (dNLR)) and irAEs was also evaluated. Results: Out of 720 pts, 456 (63%) and 143 (20%) pts presented all grade and severe irAEs respectively. Soluble factors quantification at baseline was available for 353 pts. Baseline characteristics were similar to the overall trial population. Lower levels of circulating IL-6 (cut-off: 8.7 pg/ml) at baseline were significantly associated with a higher risk of all grade irAEs (p=0.025). Lower dNLR levels (

4552 Background: The NIVOREN GETUG-AFU 26 study launched a translational research program to quantify baseline circulating soluble factors levels and correlate them with outcomes to nivolumab in mRCC pts. We previously identified on a training set (n = 80, 40 responders/40 progressors) several soluble factors significantly associated with worse overall survival (OS), progression-free survival (PFS) and response (IL-8 and VEGF), or with worse OS only (IL-6, IL-7) (Carril-Ajuria et al. ASCO GU. 2022). Our aim was to confirm these findings using an independent validation set. Methods: The remaining pts (n = 233) included in the translational-program of the NIVOREN study were included in this validation set. Based on previous results (training set), a panel of 7 different soluble factors (VEGF, VCAM-1, IL-6, IL-7, IL-8, BAFF, CXCL13) were quantified for each plasma sample using the MSD electrochemiluminescence assay. The association between baseline soluble-factors levels and response, PFS and OS was evaluated using previously identified cut-off values. Results: Two hundred thirty-three pts were included in the validation set. Baseline characteristics were similar to the overall trial population. The IMDC risk score breakdown was 17.7% good, 57.3% intermediate and 25.0% poor. With a median follow-up of 21.8 months (mo), the OS rate was 69.6% at 12 mo and median PFS was 3.0 mo. IL-8 (cut-off: 17.9 pg/ml) and IL-6 (cut-off: 8.7 pg/ml), involved in inflammation, confirmed an association with worse OS (IL8: HR = 2.57, p < 0.0001, IL-6: HR = 3.28,p < 0.0001) and worse PFS (IL-8: HR = 1.61,p = 0.0008, IL-6: HR = 1.68, p = 0.0021). VEGF (cut-off: 48.3 pg/ml) confirmed the association with worse OS (HR = 1.56, p = 0.0176), but not with PFS (p = 0.2068). IL-7, involved in T and B cells development, did not show a significant association with OS or PFS when using 8.6 pg/ml (training set) as cut-off (p = 0.0675 and p = 0.7818, respectively). IL-7 was the only cytokine to show an association with response (p = 0.044). Interestingly, circulating CXCL13 (cut-off: 106.4 pg/ml) and BAFF (cut-off: 1122.6 pg/ml), involved in B cell differentiation/survival, were significantly associated with worse OS (HR = 2.09, p = 0.0001 and HR = 2.34, p = 0.0001, respectively); BAFF showed a trend for worse PFS (HR = 1.29, p = 0.0920). Conclusions: Using the cut-off values previously identified in the training set, we confirmed a significant association between baseline blood concentration of IL-6/IL-8 and worse OS/PFS, and of VEGF with worse OS. Non-responders presented lower baseline circulating IL-7 concentrations. CXCL13 and BAFF were significantly associated with worse OS. Multivariate analyses are ongoing.

Immune checkpoint inhibitors (ICI) have been validated as an effective new treatment strategy in several tumoral types including lung cancer. This remarkable shift in the therapeutic paradigm is in large part due to the duration of responses and long-term survival seen with ICI. However, despite this, the majority of cancer patients do not experience benefit from ICI. Even among patients who initially respond to ICI, disease progression may ultimately occur. Moreover, in some patients, these drugs may be associated with new patterns of progression such as pseudo-progression and hyper-progressive disease, and different toxicity profiles with immune-related adverse events. Therefore, the identification of predictive biomarkers may help to select those patients most likely to obtain a true benefit from these drugs, and avoid exposure to potential toxicity in patients who will not obtain clinical benefit, while also reducing the economic impact. In this review, we summarize current and promising potential predictive biomarkers of ICI in patients with non-small cell lung cancer (NSCLC), as well as pitfalls encountered with their use and areas of focus to optimize their routine clinical implementation.

What is known Potentially inappropriate medication (PIM) is a risk factor for drug-related problems (DRPs) and an important inpatient safety issue. PIM-Check is a screening tool designed to detect PIM in internal medicine patients. Objective This study aimed to determine whether PIM-Check could help to identify and reduce DRPs. Method Prospective interventional study conducted on patients admitted to internal medicine wards in a university hospital between 1 September 2015 and 30 October 2015. Adult patients were included if they were hospitalized for more than 48 hours. Patients received either usual care (period 1 = control) or usual care plus medication screening by the wards' chief residents using PIM-Check (period 2 = intervention). An expert panel, composed of a clinical pharmacist, a clinical pharmacologist and two attending physicians in internal medicine, blinded to patient groups, identified DRPs. Results A total of 297 patients were included (intervention: 109). The groups' demographic parameters were similar. The expert panel identified 909 DRPs (598: control; 311: intervention). The mean number of DRPs per patient was similar in the control (3.2; 95% CI: 2.9-3.5) and intervention groups (2.9; 95% CI: 2.4-3.3) (P = .12). PIM-Check displayed 33.4% of the 311 DRPs identified in the intervention group. What is new and conclusion In this study, PIM-Check had limited value, as the average number of DRPs per person was similar in both groups. Although one-third of DRPs counted in intervention group had been identified by PIM-Check, this did not lead to a reduction in DRPs. This lack of impact of PIM-Check on drug prescription may be explained by the number of alerts displayed by the application and hospital physicians' reluctance to modify the treatments for chronic conditions previously prescribed by general practitioners.

379 Background: The NIVOREN GETUG-AFU 26 study reported safety and efficacy of nivolumab in patients with RCC in a “real world setting”. A translational research program was launched to quantify baseline cytokine levels and correlate them with outcomes to nivolumab. Methods: Extreme responder patients (pts) treated with nivolumab as part of the phase II NIVOREN GETUG-AFU 26 were included in this TRAINING cohort. A panel of 14 different plasma cytokines and proteins (VEGF, VCAM-1, IL-6, IL-7, IL-8, IL-10, APRIL, BAFF, 4-1BB, BCA, SDF-1, MDC, IFN-gamma and TNF-alpha) were quantified for each plasma sample using the Elisa-based Meso Scale Discovery electrochemiluminescence assay. The association between baseline cytokine levels and objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) was evaluated. Results: Overall, 80 pts, 40 responders and 40 progressors, were included for cytokine analysis. Baseline characteristics were similar to the overall trial population. The IMDC risk score breakdown was 11.3% good, 56.3% intermediate and 32.5% poor. With a median follow-up of 21.2 months, mOS data was immature at data cut-off. Overall survival rate was 67.3% at 12 months and median PFS was 3.8 months. Increased levels of IL-6 (75th percentile=P75), IL-7 (P75), IL-8 (P50) and VEGF (P50) were significantly negatively associated with survival (IL-6: HR=2.44, p=0.0112; IL-7: HR=2.38, p=0.0123; IL-8: HR=2.80, p=0.0045, and VEGF: HR=2.43, p=0.0133). 4-1BB (P50) was associated with improved OS (HR=0.39, p=0.0375). Higher levels of IL-8 (P50) and VEGF (P50) were associated with worse PFS (IL-8: HR=2.50, p=0.0133, and VEGF: HR=1.96, p=0.0132) and worse ORR (IL-8: p=0.013, and VEGF: p=0.044). Except for IL-8 and VEGF, no other associations with response were observed. Conclusions: Higher baseline plasma levels of IL-6, IL-7, IL-8 and VEGF were significantly associated with worse survival outcomes in mRCC pts treated with nivolumab within TRAINING cohort of the NIVOREN trial. In contrast, 4-1BB was significantly associated with improved OS. IL-8 and VEGF were also associated with worse PFS and ORR. VALIDATION cohort within the entire NIVOREN study is ongoing.

Background: The development of immune checkpoint blockade (ICB) has revolutionized the clinical outcome of renal cell carcinoma (RCC). Nevertheless, improvement of durability and prediction of responses remain unmet medical needs. While it has been recognized that antibiotics (ATBs) decrease the clinical activity of ICB across various malignancies, little is known about the direct impact of distinct intestinal nonpathogenic bacteria (commensals) on therapeutic outcomes of ICB in RCC. Objective: To evaluate the predictive value of stool bacteria composition for ICB efficacy in a cohort of advanced RCC patients. Design, setting, and participants: We prospectively collected fecal samples from 69 advanced RCC patients treated with nivolumab and enrolled in the GETUG-AFU 26 NIVOREN microbiota translational substudy phase 2 trial (NCT03013335) at Gustave Roussy. We recorded patient characteristics including ATB use, prior systemic therapies, and response criteria. We analyzed 2994 samples of feces from healthy volunteers (HVs). In parallel, preclinical studies performed in RCC-bearing mice that received fecal transplant (FMT) from RCC patients resistant to ICB (NR-FMT) allowed us to draw a cause-effect relationship between gut bacteria composition and clinical outcomes for ICB. The influence of tyrosine kinase inhibitors (TKIs) taken before starting nivolumab on the microbiota composition has also been assessed. Outcome measurements and statistical analysis: Metagenomic data (MG) from whole genome sequencing (WGS) were analyzed by multivariate and pairwise comparisons/fold ratio to identify bacterial fingerprints related to ATB or prior TKI exposure and patients’ therapeutic response (overall response and progression-free survival), and compared with the data from cancer-free donors. Results and limitations: Recent ATB use (n = 11; 16%) reduced objective response rates (from 28% to 9%, p < 0.03) and markedly affected the composition of the microbiota, facilitating the dominance of distinct species such as Clostridium hathewayi, which were also preferentially over-represented in stools from RCC patients compared with HVs. Importantly, TKIs taken prior to nivolumab had implications in shifting the microbiota composition. To establish a cause-effect relationship between gut bacteria composition and ICB efficacy, NR-FMT mice were successfully compensated with either FMT from responding RCC patients or beneficial commensals identified by WGS-MG (Akkermansia muciniphila and Bacteroides salyersiae). Conclusions: The composition of the microbiota is influenced by TKIs and ATBs, and impacts the success of immunotherapy. Future studies will help sharpen the role of these specific bacteria and their potential as new biomarkers. Patient summary: We used quantitative shotgun DNA sequencing of fecal microbes as well as preclinical models of fecal or bacterial transfer to study the association between stool composition and (pre)clinical outcome to immune checkpoint blockade. Novel insights into the pathophysiological relevance of intestinal dysbiosis in the prognosis of kidney cancer may lead to innovative therapeutic solutions, such as supplementation with probiotics to prevent primary resistance to therapy. Antibiotics prior to immune checkpoint inhibitors have a deleterious clinical impact, reduce the microbiome diversity, and increase Clostridium hathewayi bacteria associated with resistance. Higher baseline microbiome diversity and Akkermansia muciniphila are associated with longer progression-free survival. In murine fecal microbiome transplantation experiments, A. muciniphila can restore the anticancer activity of the combination of anti–PD-1 and CTLA-4.

Monoclonal antibodies in oncology, used as targeted molecular therapy, linked to cytotoxic compound or directed against immune checkpoints, feature complex PKs essentially determined by their physicochemical characteristics. The increasing number of studies shows the existence of Pharmacokinetics/Pharmacodynamic (PK/PD) relationships for many of them. Although more studies, especially conducted in early clinical phases, are needed, existing studies highlight the need to integrate PK data for monoclonal antibodies in all phases of their development and the therapeutic management of patients with cancer. The current challenge is to identify non-responders as soon as possible. The use of monoclonal antibody dosage to determine the patient's PK profile and, as a result, the disease activity profile could therefore be an early predictive marker to help physicians optimise the strategy to be pursued, including dose adjustment, prolongation of the dose interval or even discontinuation of treatment.

More than 25 therapeutic monoclonal antibodies (mAbs) used in oncology have been approved since 1997. Their nature has been largely modified through the last 20 years, from the chimeric IgG1 rituximab with pharmacokinetic parameters specific of murin or chimeric mAbs to humanized or human mAbs. Doses and administration frequency have been chosen based on this nature. More recently, the developed and registered mAbs are mostly IgG1, IgG2, IgG3 or IgG4 humanized or 100% human. Therefore, their behavior is different from the first mAbs authorized leading to lower systemic clearance and shorter half-life due to higher cellular uptake balanced by FcRn recognition with recirculation. The complexity of the pharmacokinetics and the pharmacokinetics/pharmacodynamics relation are increased for antibody-drug conjugates or bispecific T-cell engagers. However, significant number of studies reported pharmacokinetics/pharmacodynamics relations, with positive exposure-response link justifying the exploration of the pharmacokinetics in routine clinical practice of these therapeutic mAbs to prevent treatment failures and to limit their toxicities.

Resume Contexte Les prescriptions medicamenteuses inappropriees comprennent les sur-prescriptions (prescription d’un medicament non indique), les prescriptions inadaptees (choix de molecules, duree, dose inadaptes, doublon, interactions medicamenteuses potentiellement nefastes, suivi inapproprie) et les sous-prescriptions (omission d’un traitement indique). Elles constituent une cause d’evenements indesirables medicamenteux evitables et sont associees a des allongements de durees d’hospitalisation, une diminution de la qualite de vie, une augmentation de la morbimortalite, ou encore a des surcouts pour les systemes de sante. Les patients geriatriques, souvent polypathologiques et polymediques, sont a haut risque de prescriptions medicamenteuses inappropriees. Depuis une vingtaine d’annee, des outils de detection de ces prescriptions ont ete developpes, afin de diminuer ces erreurs. Objectif Cette revue a pour objectifs d’apporter un apercu comparatif et une analyse critique de ces outils explicites. Sources documentaires et selection des etudes Une recherche systematique de la litterature menee dans les bases de donnees PubMed , Embase , Cochrane Library et Google Scholar , sur la periode janvier 1991–novembre 2015, utilisant la combinaison de mots-cles : « (“inappropriate prescribing” [MeSH Terms] OR “medication errors” [MeSH Terms] AND “potentially inappropriate medications” [MeSH Terms] AND “elderly” [MeSH All field] AND “explicit criteria” [MeSH Terms]) » a permis d’inclure les article rediges en anglais ou en francais, decrivant le developpement d’une nouvelle liste de criteres explicites destinee a la geriatrie. Les caracteristiques, l’organisation et le contenu de ces dernieres sont detailles, ainsi que l’evaluation de leur validite et de leur caractere optimal pour une utilisation en geriatrie. Resultats Quatorze outils ont ete identifies. Une organisation par specialites medicales et pathologies, comme dans les grilles ACOVE, Beers version 5 et STOPP/START permet une utilisation rapide des outils. La faible redondance des criteres entre les outils suggere un manque d’exhaustivite pour certains d’entre eux. Les grilles Mimica, ACOVE, PIEA, et STOPP/START sont les plus exhaustives, seules les trois dernieres abordent les problemes de sous-prescriptions. Enfin, la capacite a detecter et diminuer les prescriptions inappropriees n’a ete evaluee que pour quelques grilles, seule STOPP/START a montre, dans le cadre d’une etude prospective, sa capacite a les diminuer.

Background & Aims Hepatitis C virus (HCV) infection is an independent risk factor for chronic kidney disease and leads to faster liver disease progression in patients requiring hemodialysis than in those with normal renal function. Little is known about the use of a sofosbuvir-containing regimen for infected patients on hemodialysis. We aimed to describe the pharmacokinetics, safety and efficacy of sofosbuvir in 2 dosing regimens and associated antiviral agents in HCV-infected patients requiring hemodialysis. Methods Multicenter, prospective and observational study of patients receiving sofosbuvir, 400mg once daily (n=7) or 3 times a week (n=5), after hemodialysis with simeprevir, daclatasvir, ledipasvir or ribavirin was conducted. Drug plasma concentrations were determined by liquid chromatography-tandem mass spectrometry before and after a 4h hemodialysis and 1.5h after last drug intake at the end of hemodialysis. Results Plasma concentrations of sofosbuvir or its inactive metabolite sofosbuvir-007 did not accumulate with either regimen between hemodialysis sessions or throughout the treatment course. Sofosbuvir-007 extraction ratio (52%) was consistent with historical data. In one patient receiving the once daily regimen, sofosbuvir-007 half-life was slightly higher (38h) than for patients with normal renal function receiving a full dose. Hemodialysis did not remove any other associated anti-HCV agents. Clinical and biological tolerance was good for all patients. Two relapses occurred with the 3 times a week regimen and none with the once daily. Conclusions A regimen including sofosbuvir, 400mg once daily, could be proposed for HCV-infected patients requiring hemodialysis and should be associated with close clinical, biological, cardiovascular, and therapeutic drug monitoring. Lay summary Hepatitis C Virus (HCV) infection in hemodialysis patients is prevalent and aggressive. Effective anti-HCV treatment in these patients may stabilize their renal disease. However, sofosbuvir, the cornerstone of most anti-HCV–containing regimens, should not be administered to these patients until more data is available. In this pharmacokinetic study, sofosbuvir full dose (400mg once daily) administered every day with another direct antiviral agent did not accumulate in hemodialysis patients and was safe and effective.

Simple Summary Immune checkpoint inhibitors (ICI) are now a cornerstone of treatment for non-small cell lung cancer (NSCLC). Despite reporting tremendous results for some patients, ICI efficacy remains reserved to a subgroup that is not yet fully characterized. Tissue based assays, such as Programmed cell death protein 1 (PD-L1) expression may enrich the responder population, but this biomarker is not always available or reliable, as responses have been observed in patients with negative PD-L1. Blood markers are hoped to be easier to access and follow, and to give an insight on patient’s immune status and tumor as well. To date, several papers have been looking for circulating biomarkers that are focused on tumor cells or host specific or general immunity in NSCLC treated with ICI. In this article, we review these circulating biomarkers in peculiar circulating immune cell, tumor related cell and soluble systemic marker. We describe the available data and comment on the technical requirements and limits of these promising techniques. Abstract Immune checkpoint inhibitors are now a cornerstone of treatment for non-small cell lung cancer (NSCLC). Tissue-based assays, such as Programmed cell death protein 1 (PD-L1) expression or mismatch repair deficiency/microsatellite instability (MMRD/MSI) status, are approved as treatment drivers in various settings, and represent the main field of research in biomarkers for immunotherapy. Nonetheless, responses have been observed in patients with negative PD-L1 or low tumor mutational burden. Some aspects of biomarker use remain poorly understood and sub-optimal, in particular tumoral heterogeneity, time-evolving sampling, and the ability to detect patients who are unlikely to respond. Moreover, tumor biopsies offer little insight into the host’s immune status. Circulating biomarkers offer an alternative non-invasive solution to address these pitfalls. Here, we summarize current knowledge on circulating biomarkers while using liquid biopsies in patients with lung cancer who receive treatment with immune checkpoint inhibitors, in terms of their potential as being predictive of outcome as well as their role in monitoring ongoing treatment. We address host biomarkers, notably circulating immune cells and soluble systemic immune and inflammatory markers, and also review tumor markers, including blood-based tumor mutational burden, circulating tumor cells, and circulating tumor DNA. Technical requirements are discussed along with the current limitations that are associated with these promising biomarkers.

Idiopathic CD4 lymphopenia (ICL) is a rare heterogeneous immunological syndrome of unclear etiology. ICL predisposes patients to severe opportunistic infections and frequently leads to poor vaccination effectiveness. Chronic immune activation, expansion of memory T cells, and impaired T-cell receptor (TCR) signaling have been reported in ICL, but the mechanistic and causative links remain unclear. We show that late-differentiated T cells in 20 patients with ICL displayed defective TCR responses and aging markers similar to those found in T cells from elderly subjects. Intrinsic T-cell defects were caused by increased expression of dual-specific phosphatase 4 (DUSP4). Normalization of DUSP4 expression using a specific siRNA improved CD4(+) T-cell activity in ICL, as this restored TCR-induced extracellular signal-regulated kinase activation and increased the expression of the costimulatory molecules CD27 and CD40L. Conversely, repeated TCR stimulation led to defective signaling and DUSP4 overexpression in control CD4(+) T cells. This was associated with gradual acquisition of a memory phenotype and was curtailed by DUSP4 silencing. These findings identify a premature T-cell senescence in ICL that might be caused by chronic T-cell activation and a consequential DUSP4-dependent dampening of TCR signaling.

Background The NIVOREN GETUG-AFU 26 study reported safety and efficacy of nivolumab in patients with RCC in a “real world setting”. A translational research program was launched to characterize immune cell populations in fresh whole blood at baseline and after 2 months of treatment (C3) to determine association with high-grade toxicity and clinical outcome. Methods Absolute number of 106 immune cell populations were analysed in patients treated at a single institution as part of the NIVOREN GETUG-AFU 26 in fresh whole blood using dry formulation panels for multicolor flow cytometry. Predefined clinical endpoints were 6-month grade 3-4 toxicity (treatment related adverse event, TRAE) occurrence and 6-month disease progression occurrence. Missing values were imputed using multivariate imputation by chained equations. Multivariate differential count analysis was done using the DESeq2 R package. Results Overall 44 patients were included in this fresh whole blood immune-monitoring. Higher occurrence of grade 3-4 TRAE at 6 months was observed in patients with lower number of CD4+PD-1neg4.1BB+ T cell (non-exhausted activated CD4 T cells) counts at baseline (log2 fold change (LFC) = -1.993 95% confidence interval (95%CI)[-2.172; -1.815] ) and with lower number of CD56+ T cells (NKT cells) at C3 (LFC = -1.464 95%CI[-1.597; -1.331]). Higher occurrence of disease progression at 6-month was observed in patients with lower number of CD4+PD-1posCD69+ T cells (exhausted activated CD4 T cells) (LFC = -1.186 95%CI[ -1.308; -1.064 ]) and with higher number of CD4+CD244+ T cells (exhausted CD4 T cells) (LFC = 1.686 95%CI[ 1.533; 1.840]) at baseline. No immune cell populations were associated with the occurrence of a 6-month progression during the course of nivolumab (C3). Conclusions Fresh whole blood monitoring at baseline and after 2 months of nivolumab identified immune cell populations associated with grade 3-4 TRAE (CD4+PD-1neg4.1BB+ T cells and CD56+ T cells) and disease progression (CD4+PD-1posCD69+ T cells and CD4+CD244+ T cells). Functional analyses and external validation are ongoing. Clinical trial identification NCT03013335. Legal entity responsible for the study UNICANCER. Funding Bristol-Myers Squibb. Disclosure B. Beuselinck: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS. B. Escudier: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: Ipsen; Advisory / Consultancy: EUSA; Advisory / Consultancy, Research grant / Funding (institution): Aveo. L. Albiges: Advisory / Consultancy, compensated to institution: Pfizer; Advisory / Consultancy, compensated to institution: Novartis; Advisory / Consultancy, compensated to institution: Roche; Advisory / Consultancy, compensated to institution: Bristol-Myers Squibb; Advisory / Consultancy, compensated to institution: IPSEN; Advisory / Consultancy, compensated to institution: MSD; Advisory / Consultancy, compensated to institution: AstraZeneca. All other authors have declared no conflicts of interest.

Contexte : Dans le cadre de l’amelioration de la prise en charge medicamenteuse du patient sous anticoagulants oraux et de la prevention de l’iatrogenie, la pharmacie de l’hopital Antoine Beclere a mis en pl ace, depuis 2009, des « Consultations antivitamines K (AVK) » aupres des patients hospitalises. But : Rapporter l’elaboration et l’evaluation preliminaire d’un dispositif de formation aux consultations AVK. Materiels et methode : Un groupe de travail de pharmaciens a elabore un dispositif pedagogique s’articulant autour d’un apprentissage theorique (savoir declaratif) et pratique (capacites, habiletes, aptitudes). Pour formaliser la methode, une fiche de projet pedagogique a elaboree. Des outils de formation et d’evaluation ont ete crees. Resultats : Le parcours de formation est divise en cinq etapes : pre-evaluation des connaissances ; formation theorique reprenant contexte et points-cles de la consultation ; atelier de mise en situation patient fictif/pharmacien ; reevaluation des connaissances ; consultations pratiques en supervision directe. Trente-quatre etudiants ont suivi cette formation. La comparaison des evaluations a montre une progression individuelle significative des scores d’apprentissage. Toutes les personnes formees ont ete validees apres deux evaluations pratiques. L’enquete de satisfaction a montre une satisfaction de 100 % des participants. Conclusion : Au regard des resultats obtenus, un impact positif du dispositif de formation elabore peut-etre tenu comme avere. Un programme e-learning est en cours de developpement afin de systematiser la formation a ces consultations et de l’elargir a toute l’equipe pharmaceutique du groupe hospitalier Paris-Sud.

Background Drug related problems (DRPs) are important issues for inpatient safety and may contribute to adverse drug events and hospital costs. Potentially inappropriate medication (PIM), including over prescription (medication without a valid indication), under prescription (failure to prescribe a clinically indicated drug) and mis-prescription (unwanted drug interaction; incorrect prescribing) is a risk factor for DRPs. PIM-Check (www.pimcheck.org), a prescription screening checklist, was recently developed to detect PIM in internal medicine patients. Purpose This study aimed to determine if electronic application of PIM-Check, used by physicians, can decrease DRPs in internal medicine patients. Material and methods This was an open label prospective study, conducted in two consecutive periods of 1 month, in patients admitted for ≥48 hours to seven internal medicine wards in a university hospital. In period 1, patients were treated with usual care (control group). In period 2, patients were treated with usual care preceded by a medication review performed by chief residents within 24 hours after admission using the PIM-Check electronic application (intervention group). At 48 hours, all medications, laboratory results, comorbidities and diagnoses were collected. DRPs were identified by a ‘gold standard’ group, composed of a clinical pharmacist, clinical pharmacologist and two internal medicine consultants, analysing all patient datasets (blinded to period group). Results 297 patients were included: 188 in the control group and 109 in the intervention group. 909 DRPs (mean/patient ±SD: 3.1±2.2) were identified: 3.2±2.2 in the control group and 2.9±2.2 in the intervention group (p=0.21). Both groups were comparable (age, sex, number of drugs, comorbidities) and had similar mean DRPs/patient. The top 5 active compounds involved in DRPs were: esomeprazole, paracetamol, tobacco, aspirin and thiamine. In the intervention group, the mean number of statements suggested by PIM-Check was 13.9±7/patients. Among the 311 DRPs identified in this group, 33.4% were suggested by PIM-Check but no treatment modifications were performed by prescribers. Conclusion PIM-Check allowed identification of one-third of DRPs. However, the number of DRPs did not decrease significantly in the intervention group. This lack of impact may be explained by the high number of statements displayed and the reluctance of hospital physicians to modify the treatment plan established by the general practitioner for chronic medical conditions, especially in the first 48 hours of hospitalisation. No conflict of interest

International audience; Lenalidomide, an oral immunomodulating agent, has shown promising activity in HIV-infected individuals with Kaposi's sarcoma (KS). This single-arm, multicenter, open-label, Gehan's two-stage phase II trial evaluated the efficacy and safety of lenalidomide in HIV-infected patients with progressive KS despite previous chemotherapy (NCT01282047, ANRS 154 Lenakap trial). The primary endpoint was the rate of partial response (PR) or complete response (CR) at week 24, evaluated by both the study investigators and the patients using the Physical Global Assessment (PGA). AIDS Clinical Trials Group (ACTG) criteria for KS treatment evaluation were used as a secondary endpoint. The data and safety monitoring board recommended that enrollments be halted on April 24, 2013, because of lack of responses. We enrolled 12 antiretroviral-treated HIV-infected men with progressive KS despite previous chemotherapy. Their HIV plasma viral load was

Background and objectives Drug related problems (DRPs) are important issues for inpatient safety and may conduct to adverse drug events, increase length of stay and hospital costs. Potentially inappropriate medication (PIM) including over-prescription (medication without a valid indication or with contra-indication), under-prescription (failure to prescribe a clinically indicated drug) and mis-prescription (unwanted drug- interaction; incorrect prescribing) is a risk factor for DRPs. Several tools have recently been developed to target PIM. One of them, PIM-Check©, is dedicated to internal medicine patients. The aim of this study was to determine if PIM-Check© electronic application, used by physicians, can decrease DRPs in internal medicine patients. Methods Open label, 2 consecutive periods of one month, prospective study, conducted on patients admitted for more than 48 h in 7 internal medicine wards in a university hospital. In period 1, patients were treated with usual care (control group). In period 2, patients were treated with usual care preceded by a medication review performed by chief residents within 24 h after admission using PIM-Check© electronic application (intervention group). At 48 h, all medications, lab results, comorbidities and active diagnosis were collected for each patient. DRPs were identified by a “gold standard” group, composed of a clinical pharmacist, a clinical pharmacologist and two attending-physicians of internal medicine analysing all patients-dataset (blinded to period group). Results Two hundred ninety-seven patients were included: 188 in control group and 109 in intervention group. A total of 909 DRPs (mean/patient ± SD: 3.1 ± 2.2) were identified: 3.2 ± 2.2 in control group and 2.9 ± 2.2 in intervention group (P-value 0.21). Both groups were comparable (age, sex, number of drugs, co-morbidities) and had similar mean of DRPs/patients. Top 5 active compound involved in DRPs were: esomeprazole, paracetamol, tobacco, aspirin and thiamine. In the intervention group, the mean number of statements suggested by PIM-Check© was 13.9 ± 7/patients. Among the 311 DRPs identified in this group, 33.4% (n = 104) were suggested by PIM-Check©, but no treatment modification were performed. Discussion and conclusions PIM-Check© allowed identifying one third of DRPs approved by a gold standard group. However, the number of DRPs did not decrease in the intervention group when physicians used PIM-Check©. The high number of statements displayed by the electronic application, and the hesitancy of hospital physicians to change treatment associated with chronic medical conditions, especially in the first 48 h of hospitalization may explain the lack of impact on the number of DRPs.

Potentially inappropriate prescriptions include over-prescription, which refers to prescription of more drugs than clinically needed, mis-prescription which refers to incorrect prescription of a drug that is needed (as per drug, dose, drug interactions, duration of therapy, duplication, follow-up, etc.) and under-prescription which stands for failure to prescribe drugs that are needed. They are associated with adverse drug events, increased use of health-care services, morbimortality and health-care costs, and poorer quality of life. Due to polymorbidity and polypharmacy, potentially inappropriate prescription is common among the elderly. In the last 2 decades, explicit indicators to detect inappropriate prescriptions were developed in geriatrics.The aim of this review is to summarize, compare and critically review existing explicit criteria.We conducted a systematic literature search in PubMed, Embase, Cochrane Library and Google Scholar, from January 1991 to November 2015. The following keywords were used: "("inappropriate prescribing" [MeSH Terms] OR "medication errors" [MeSH Terms] AND "potentially inappropriate medications" [MeSH Terms] AND "elderly" [MeSH All field] AND "explicit criteria" [MeSH Terms])". Articles describing the development of new list of explicit indicators dedicated to geriatrics, in English and in French, were included in this review. Their characteristics, organization, content, and assessments of their validity and of the optimal tool for geriatrics are presented.Fourteen lists of explicit indicators were included in the review. An organization based on physiological systems and pathologies, as observed in ACOVE, 5th version of Beers criteria and STOPP/START enables quick application in general practice. A low overlap among criteria was observed between tools. This may be due to a lack of completeness for some tools. Mimica, ACOVE, PIEA, and STOPP/START are the most exhaustive ones, only the last three addressing the under-prescription issue. Finally, the ability to detect and reduce inappropriate prescriptions has only been evaluated for few tools; STOPP/START is the only one, which has demonstrated its ability to reduce them in a prospective study.

We describe the pharmacokinetics of dolutegravir (DTG) in a premature neonate after maternal intensification of an antiretroviral (ARV) regimen by adding DTG. During the last 2 weeks of pregnancy, the ARV was tenofovir-emtricitabine, atazanavir-ritonavir, and DTG (50 mg once daily). From the interaction between atazanavir and DTG via CYP3A4 and UGT1A1 and placental efflux transporter inhibition and considering the infant's probable enzymatic immaturity, the DTG elimination half-life was estimated to be 4-fold longer in neonates than in adults.

Objectives Potentially inappropriate medication (PIM) occurs frequently and is a well-known risk factor for adverse drug events, but its incidence is underestimated in internal medicine. The objective of this study was to develop an electronic prescription-screening checklist to assist residents and young healthcare professionals in PIM detection. Design Five-step study involving selection of medical domains, literature review and 17 semistructured interviews, a two-round Delphi survey, a forward/back-translation process and an electronic tool development. Setting 22 University and general hospitals from Canada, Belgium, France and Switzerland. Participants 40 physicians and 25 clinical pharmacists were involved in the study. Agreement with the checklist statements and their usefulness for healthcare professional training were evaluated using two 6-point Likert scales (ranging from 0 to 5). Primary and secondary outcome measures Agreement and usefulness ratings were defined as: >65% of the experts giving the statement a rating of 4 or 5, during the first Delphi-round and >75% during the second. Results 166 statements were generated during the first two steps. Mean agreement and usefulness ratings were 4.32/5 (95% CI 4.28 to 4.36) and 4.11/5 (4.07 to 4.15), respectively, during the first Delphi-round and 4.53/5 (4.51 to 4.56) and 4.36/5 (4.33 to 4.39) during the second (p

Introduction et objectifs Le risque d’erreurs medicamenteuses est accru a l’admission d’un service de soins. L’interface ville/hopital expose a un risque de discontinuite dans la prise en charge medicamenteuse en induisant des divergences non intentionnelles de prescription (DNI) entre traitements habituels et hospitaliers. L’objectif de cette etude etait d’evaluer l’incidence des DNI et de mesurer l’impact d’une reconciliation medicamenteuse a l’admission sur la justesse de la prescription hospitaliere en medecine interne. Methodes Etude interventionnelle de 2 mois realisee a l’admission des patients en medecine interne dans le cadre du projet national « Progress ! La securite de la medication aux interfaces ». Tous les patients admis etaient eligibles et etaient inclus apres la redaction de la prescription initiale hospitaliere (PIH). Un pharmacien realisait la meilleure anamnese medicamenteuse possible (MAMP), puis procedait a l’identification des divergences de prescription par la comparaison de ces donnees aux traitements de la PIH. L’intentionnalite des divergences etait determinee par une concertation avec les prescripteurs et les DNI etaient evaluees pour leur type et les classes therapeutiques qu’elles concernaient. Resultats Vingt-sept patients (59 % femmes) ont ete inclus. L’âge moyen etait de 64,6 ± 17,5 ans. En moyenne, la MAMP durait 1 heure, etait effectuee dans un intervalle de 1,4 jours apres l’admission et permettait l’identification de 7,6 ± 4,9 lignes de traitements par l’exploitation de 2 sources d’information (le plus souvent le patient et son officine). Un total de 54 divergences, dont 42 DNI concernant 17 patients ont ete identifiees (1,6 DNI par patient). Les DNI etaient des omissions de prescription ( n = 32), des erreurs de posologie ( n = 7), des erreurs de modalites d’administration ( n = 2) et une erreur de nom de specialite. Les DNI interessaient 11 classes therapeutiques et 81 % ( n = 34) concernaient 5 classes, (systeme digestif, nerveux, respiratoire, cardiovasculaire et organes sensoriels). La concertation avec le prescripteur a permis la rectification de 52 % des DNI ( n = 22). Discussion et conclusions Les divergences de prescription sont frequentes a l’admission et la reconciliation medicamenteuse peut permettre l’interception et la correction des DNI. L’impact de cette derniere pourra etre mieux estime par une appreciation de la gravite clinique potentielle des DNI par un groupe d’experts independants (medecins, pharmacien clinicien). Un impact positif serait un argument en faveur d’une intervention plus systematique des pharmaciens en amont de la redaction de la PIH, afin de prevenir la survenue des DNI.

Recent studies have highlighted the importance of understanding the molecular determinants of CXCL12-mediated effects in cancers. Once previously thought to interact exclusively with CXCR4, CXCL12 also binds with high affinity to CXCR7 (recently renamed ACKR3), which belongs to an atypical chemokine receptor family whose members fail to activate Gαi proteins but interact with β-arrestins. In addition to its capacity to control CXCL12 bioavailability, ACKR3 can either enhance or dampen CXCR4-mediated signaling and activity. In light of the most recent findings, we have examined the role of ACKR3 in cancer, including a subset of virus-related cancers.

Introduction et objectifs Les prescriptions medicamenteuses inappropriees (PMI), regroupant les sur-/sous-prescriptions, interactions (IAM) et mauvais choix de traitement sont des facteurs de risque d’evenements indesirables medicamenteux (EIM). L’utilisation de grilles de criteres explicites en geriatrie a permis de reduire les PMI dans cette population. A notre connaissance, aucun outil comparable destine a l’ensemble des patients de medecine interne n’a ete developpe. Developper un outil francophone international de detection des PMI adapte a l’adulte hospitalise en medecine interne. Methodes Apres une revue de la litterature, nous avons realise 17 entretiens semi-structures avec des medecins specialistes et elabore une liste initiale d’items visant a detecter les PMI pour chaque grande specialite de medecine. Cette liste a ete validee selon une methode Delphi a 2 tours, par 40 internistes et pharmaciens cliniciens, de centres hospitaliers universitaires et generaux de la francophonie (Be, CH, Fr, Quebec). Les experts devaient indiquer leur niveau d’accord avec les items selon une echelle de 1 a 5 (pas du tout a totalement d’accord). Au 1er tour, seuls les items ayant obtenu une note ≥ 4 par > 65 % des experts etaient conserves, puis ± modifies pour le 2e tour. Seuls ceux ayant obtenu une note ≥ 4 par > 75 % des experts au 2e tour etaient integres a l’outil final. Resultats Le taux de participation au Delphi a ete de 97,5 % (39/40). La liste initiale soumise au 1er tour comprenait 166 items dont 6 ont ete supprimes, 6 fusionnes et 3 ajoutes. Cent pour cent des items du 2e tour ont ete valides. Les moyennes d’accord avec les items aux 1er et 2e tours etaient respectivement de 4,32 et 4,53 (p Discussion et conclusions Cette grille est le 1er outil francophone, international de detections des PMI en medecine interne. Nous souhaitons qu’il s’integre a l’ensemble des dispositifs utiles a la reduction des EIM et qu’il aide a la formation des internes en medecine et pharmacie. Afin de faciliter son usage, un site Internet et une version mobile de l’outil sont en developpement. Une etude de validation de l’outil dans la pratique sera ensuite menee.

To illustrate the potential benefits of ward-based clinical pharmacy, the case is reported of a patient who benefited from three successful pharmaceutical interventions. The patient visited the emergency department with an epigastric pain and a vitamin K antagonist overdose was suspected. Prothrombin complex concentrates were prescribed by the emergency physician. Analysis of the patient9s parameters did not show evidence of any sign of major bleeding so the order was cancelled after the intervention of the on-call pharmacy resident. Medication reconciliation performed by another resident showed two major unintended discrepancies: vigabatrin prescription had been omitted and sotalol was prescribed at the wrong dose. The physician was informed and the prescription order corrected. Eventually the pharmacy resident responsible for anticoagulant therapy education visited the patient. Careful investigation of the patient9s medical chart led him to suggest discontinuation of the anticoagulant therapy. This intervention resulted in the immediate discharge of the patient. This case report highlights the added value of pharmaceutical care performed on the ward and illustrates both the clinical benefit for the patient and the economic benefit for the hospital. This topic is rarely discussed in case reports. This paper demonstrates its value and argues to extend its practice.

Background The 2007 WHO guidelines underscore the importance of using medicines reconciliation (MR) in hospitals in order to assure the correct medicines at transitions in care. Purpose To develop a process-oriented approach in order to implement a MR process in an abdominal surgery ward. Materials and methods This study was divided into three parts of 1 month each. First, The authors compared the medicines history (MH) taken by the pharmacist with the physician9s computerised prescription at admission. Unintended medication errors (UMD) were identified with the physician in order to obtain the mean number of UMD per patient. In the second study, the MH taken by the pharmacist was copied onto an MH form (MHF) that was used by the practitioner to help prescribe treatment at admission. Before beginning the third part, the MR process workflow was optimised by a multi-disciplinary working team. In the second and third part the average days to complete MHF and the mean number of UMD per patient were measured in order to assess the efficiency of our MR process. Results 44 (average age 53, 3.4 treatments/patient), 50 (average age 50.5, 2.9 treatments/patient) and 55 (average age 48.3, 2.3 treatments/patient) patients were included in parts 1, 2 and 3 respectively. UMDs per patient decreased from 0.41 in part 1 to 0.24 in part 2 and 0.25 in part 3. Workflow optimisation before the third part led to the pharmacist performing MHF for scheduled patients before their admission. Average days to complete the MHF decreased from 1.1 to 0.82 between parts 2 and 3. Conclusions Our approach, which was to introduce small improvements, communicate actively with the clinical unit and improve the workflow enabled us to successfully introduce MR into the abdominal surgery unit. The MR process now relies on a structured organisation and no longer on individuals.