Efficacy and safety of NI-0101, an anti-toll-like receptor 4 monoclonal antibody, in patients with rheumatoid arthritis after inadequate response to methotrexate: a phase II study

Objectives Anti-citrullinated protein antibodies (ACPAs) form immune complexes with citrullinated proteins binding toll-like receptor (TLR) 4, which has been proposed as a mediator of rheumatoid arthritis (RA). NI-0101 is a first-in-class humanised monoclonal antibody blocking TLR4, as confirmed by inhibition of in vivo lipopolysaccharide-induced cytokine release in healthy volunteers. This study was design to confirm preclinical investigations supporting a biomarker-driven approach for treatment of patients with RA who present positive for these immune complexes. Methods Placebo-controlled, double-blind, randomised (2:1) trial of the tolerability and efficacy of NI-0101 (5 mg/kg, every 2 weeks for 12 weeks) versus placebo in ACPA-positive RA patients with inadequate response to methotrexate. Efficacy measures included Disease Activity Score (28-joint count) with C reactive protein (DAS28-CRP), European League Against Rheumatism (EULAR) good and moderate responses, and American College of Rheumatology (ACR) 20, ACR50 and ACR70 responses. Subgroup analyses defined on biomarkers were conducted. Pharmacokinetics, pharmacodynamics and safety were reported. Results 90 patients were randomised (NI-0101 (61) and placebo (29)); 86 completed the study. No significant between-group difference was observed for any of the efficacy endpoints. Subgroup analyses using baseline parameters as covariants did not reveal any population responding to NI-0101. Treatment-emergent adverse events occurred in 51.7% of patients who received placebo versus 52.5% for NI-0101. Conclusions We demonstrate for the first time that in RA, a human immune-mediated inflammatory disease, blocking the TLR4 pathway alone does not improve disease parameters. Successful targeting of innate immune pathways in RA may require broader and/or earlier inhibitory approaches

Characteristics of Positive Deviants in Western Chimpanzee Populations

With continued expansion of anthropogenically modified landscapes, the proximity between humans and wildlife is continuing to increase, frequently resulting in species decline. Occasionally however, species are able to persist and there is an increased interest in understanding such positive outliers and underlying mechanisms. Eventually, such insights can inform the design of effective conservation interventions by mimicking aspects of the social-ecological conditions found in areas of species persistence. Recently, frameworks have been developed to study the heterogeneity of species persistence across populations with a focus on positive outliers. Applications are still rare, and to our knowledge this is one of the first studies using this approach for terrestrial species conservation. We applied the positive deviance concept to the western chimpanzee, which occurs in a variety of social-ecological landscapes. It is now categorized as Critically Endangered due to hunting and habitat loss and resulting excessive decline of most of its populations. Here we are interested in understanding why some of the populations did not decline. We compiled a dataset of 17,109 chimpanzee survey transects (10,929 km) across nine countries and linked them to a range of social and ecological variables. We found that chimpanzees seemed to persist within three social-ecological configurations: first, rainforest habitats with a low degree of human impact, second, steep areas, and third, areas with high prevalence of hunting taboos and low degree of human impact. The largest chimpanzee populations are nowadays found under the third social-ecological configuration, even though most of these areas are not officially protected. Most commonly chimpanzee conservation has been based on exclusion of threats by creation of protected areas and law enforcement. Our findings suggest, however, that this approach should be complemented by an additional focus on threat reduction, i.e., interventions that directly target individual human behavior that is most threatening to chimpanzees, which is hunting. Although changing human behavior is difficult, stakeholder co-designed behavioral change approaches developed in the social sciences have been used successfully to promote pro-environmental behavior. With only a fraction of chimpanzees and primates living inside protected areas, such new approaches might be a way forward to improve primate conservation

Mise en place de l'imagerie embarquée au Centre Jean Perrin

L'installation dans le département de radiothérapie du Centre Jean Perrin de 2 nouveaux accélérateurs équipés d'imagerie embarquée (tomographie conique Cone Beam CT kV) a motivé une évaluation de l'outil et une modification des pratiques de contrôle de positionnement au poste de traitement. La mise en pratique du contrôle du positionement du patient par 2 clichés orthogonaux les 3 premiers jours puis de façon hebdomadaire, a été étendue à tous les postes de traitements, avec une systématisation de la conduite à tenir en cas de modification par rapport aux marges attendues. La mise en œuvre de ces contrôles mobilise 3h de temps médical par jour et une partie de cette étude a consisté à évaluer la possibilité de réaliser une délégation partielle de ces contrôles. Dans 96,7% des cas l'écart des mesures est <=3mm ce qui permettrait de déléguer ce contrôle aux MER. Une deuxième partie de ce travail a été l'analyse du Cone Beam CT en ORL et sur la prostate. En ORL, l'analyse confirme qu'il existe des mouvements de la tête dans le masque et que ces derniers s'accentuent à la 4ème semaine au moment de la perte de poids du patient. En fin d'irradiation il existe une diminution du volume des parotides, associée à une augmentation de la dose reçue aux parotides et à la moelle. Les doses reçues par le rectum lors d'une irradiation prostatique sont supérieures à la dosimétrie prévisionnelle et peuvent être corrigées par un recalage osseux optimal. Les fiduciaires ou le CBCT devraient permettre de réduire la dose au rectum surtout en cas d'escalade de dose. L'utilisation en pratique de routine du Cone beam CT n'est pas encore utilisable car il demande du temps médecin et machine supplémentaire.CLERMONT FD-BCIU-Santé (631132104) / SudocSudocFranceF

Drugs and Cancer: an Analysis of the French Pharmacovigilance Database

Background. Our knowledge on cancers related to drugs remains limited. Among the different pharmacoepidemiological approaches assessing this risk, analysis of reports to pharmacovigilance (PV) system is uncommon. Objectives. To review cancers registered as adverse drug reactions (ADRs) in the French Pharmacovigilance Database (FPVDB). Methods. This study was based on spontaneous reports of ADRs submitted to the French PV system. All cases of cancers reported in the FPVDB between 1995 and 2006 were reviewed. Cases with transgenerational effects, cases from patients with an history of primary cancer and cancers associated with antineoplastic drugs were excluded. Drugs were classified according ATC classification. Results. Out of 207 000 notifications, 414 cases of cancer (998 citations of drugs) were identified. Report s increased from 19 cases in 1995 to 70 in 2006. Patients’ age ranged from 2 to 95 years. Gender was equally distributed. Most frequently reported cancers were lymphomas (22.7%), b asal or squamous cell carcinomas (16.4%) and leukemias (13.8%). Immunosuppressants (37.6%) were ranked in the first position followed by corticosteroids (9.3%). Potential drug-cancer associations, previously described in the literature (immunosuppressants, hydroxycarbamide, mitoxantrone, cyproterone and hormone replacement therapy) were found in the database. Other potential drug-cancer associations (leukemia and non-Hodgkin’s lymphoma after exposition to nucleoside reverse-transcriptase inhibitors or interferon) were also identified. Conclusions. Cancer notifications in a PV database, although usually considered as poorly generalizable to the general population, appears to be useful in the surveillance of cancer risk associated to drugs. It allows both confirmation of already known data and detection of new signals. Combination of present data with pharmacoepidemiological studies and collaborations with cancer registries would allow better identification of these risk signals

Drug interactions between antihypertensive drugs and non-steroidal anti-inflammatory agents: a descriptive study using the French Pharmacovigilance database

International audienceDrug-drug interactions (DDIs) between antihypertensive drugs and non-steroidal anti-inflammatory drugs (NSAIDs) can lead to adverse drug reactions (ADRs). Guidelines are available to help prescribers deal with these drug associations, but their implementation is not well evaluated. The aims of this study were to assess the prevalence of NSAIDs exposure in patients treated with antihypertensive drugs, using the French Pharmacovigilance database, and explore the ADRs related to DDIs between antihypertensive drugs and NSAIDs. Over the 11, 442 notifications of ADRs recorded in this database in patients treated with oral antihypertensive drugs between 2008 and 2010, 517 (4.5 and 95% CI: 4.1-4.9) also included exposure to NSAIDs. These subjects were more frequently women, took more drugs in general, and were younger and less frequently treated with antiplatelet drugs. In 24.2% of them (125 patients), a DDI between NSAIDs and antihypertensive drugs was potentially the cause of the reported ADR. Acute renal failure caused by DDIs between NSAIDs and angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), or diuretics was the most frequently reported ADR (20.7%). Finally, in the French Pharmacovigilance database, around one-fourth of associations NSAIDs + antihypertensive drugs are associated with a 'serious' ADR (mainly acute renal failure), suggesting that this well-known DDI is not enough taken into account by prescribers

More on the “Triple Whammy”: antihypertensive drugs, non-steroidal anti-inflammatory agents and acute kidney injury – a case/non-case study in the French pharmacovigilance database

International audienceIt has been suggested that the risk of acute kidney injury (AKI) increases with the number of drugs associated between non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin converting enzyme inhibitors (ACEis) [or angiotensin receptor blockers (ARBs)] and diuretics. We aimed to investigate whether the number of drugs associated between NSAIDs, ACEis, ARBs and diuretics was associated to disproportionate reporting of AKI in the French Pharmacovigilance Database. In reports of Adverse Drug Reactions (ADRs) recorded between 01 January 2008 and 31 December 2010, we selected patients whose medications included at least one oral antihypertensive drug. We used a case/non-case methodology. Cases were AKI and non-cases were all the remaining reports. Among the 11,442 ADR reports in patients under antihypertensive drug recorded in the French Pharmacovigilance Database, 837 ADRs were AKI (7.3%, 95% CI 6.8-7.8). AKI and the number of drugs associated were disproportionately reported (one drug alone: adjusted ROR 2.19, 95% CI: 1.65-2.89, two drugs: adjusted ROR 5.27, 95% CI: 4.00-6.94, three and more: adjusted ROR 16.46, 95% CI: 11.38-23.80). There was no significant association between NSAIDs' half-lives and reporting of AKI (adjusted ROR=0.54, 95% CI: 0.25-1.15). Given the widespread use of these hazardous drugs in general population, caution is needed when they are associated

Intraprostatic Fiducials Compared with Bony Anatomy and Skin Marks for Image-Guided Radiation Therapy of Prostate Cancer

International audiencePurpose Prostate motion occurs during radiotherapy for localized prostate cancer. We evaluated the input of intraprostatic fiducials for image-guided radiation therapy and compared it with bony anatomy and skin marks. Methods Eleven patients were implanted with three fiducial markers in the prostate. Daily sets of orthogonal kV-kV images were compared with digitally reconstructed radiography. Data were recorded for skin marks, bony anatomy, and fiducial markers. The variations were analyzed along three principal axes (left-right: LR, superoinferior: SI, and anteroposterior: AP). Results A total of 2,417 measures were recorded over 38 fractions of radiotherapy (76 Gy). Fiducial marker movements from bony anatomy were ≤ 5 mm for 84.2% (confidence interval: CI 95%±1.5), 91.3% (CI 95%±1.1), and 99.5% (CI 95%±0.4) of the measures along the AP, SI, and LR axes, respectively. Ninety-five percent of the shifts between a fiducial marker and the bony anatomy were < 8 mm in the AP and SI axes, and < 3 mm in the LR axis. Fiducial marker movements from skin marks were ≤ 5 mm for 64.8% (CI 95%±1.9), 79.2% (CI 95%±1.6), and 87.2% (CI 95%±1.3) of the measures along the AP, SI, and LR axes, respectively. Bony anatomy movements from skin marks were ≤ 5 mm for 84% (CI 95%±1.4), 92% (CI 95%±1.1), and 87% (CI 95%±1.3) of the measurements along the AP, SI, and LR axes, respectively. Conclusion Using fiducial markers provides better accuracy of repositioning of the prostate than using bony anatomy and skin marks for image-guided radiotherapy of prostate cancer