QoLR: An R Package for the Longitudinal Analysis of Health-Related Quality of Life in Oncology

Health-related quality of life has become increasingly important in clinical trials over the past two decades. The R package QoLR is a recently developed package for the longitudinal analysis of health-related quality of life in oncology. This package contains the scoring of most of the European Organisation for Research and Treatment of Cancer quality of life questionnaires and some programs to analyze the time to a health-related quality of life score deterioration as a modality of longitudinal analysis in oncology

Parasite fate and involvement of infected cells in the induction of CD4+ and CD8+ T cell responses to Toxoplasma gondii

During infection with the intracellular parasite Toxoplasma gondii, the presentation of parasite-derived antigens to CD4+ and CD8+ T cells is essential for long-term resistance to this pathogen. Fundamental questions remain regarding the roles of phagocytosis and active invasion in the events that lead to the processing and presentation of parasite antigens. To understand the most proximal events in this process, an attenuated non-replicating strain of T. gondii (the cpsII strain) was combined with a cytometry-based approach to distinguish active invasion from phagocytic uptake. In vivo studies revealed that T. gondii disproportionately infected dendritic cells and macrophages, and that infected dendritic cells and macrophages displayed an activated phenotype characterized by enhanced levels of CD86 compared to cells that had phagocytosed the parasite, thus suggesting a role for these cells in priming naïve T cells. Indeed, dendritic cells were required for optimal CD4+ and CD8+ T cell responses, and the phagocytosis of heat-killed or invasion-blocked parasites was not sufficient to induce T cell responses. Rather, the selective transfer of cpsII-infected dendritic cells or macrophages (but not those that had phagocytosed the parasite) to naïve mice potently induced CD4+ and CD8+ T cell responses, and conferred protection against challenge with virulent T. gondii. Collectively, these results point toward a critical role for actively infected host cells in initiating T. gondii-specific CD4+ and CD8+ T cell responses

Search for stop and higgsino production using diphoton Higgs boson decays

Results are presented of a search for a "natural" supersymmetry scenario with gauge mediated symmetry breaking. It is assumed that only the supersymmetric partners of the top-quark (stop) and the Higgs boson (higgsino) are accessible. Events are examined in which there are two photons forming a Higgs boson candidate, and at least two b-quark jets. In 19.7 inverse femtobarns of proton-proton collision data at sqrt(s) = 8 TeV, recorded in the CMS experiment, no evidence of a signal is found and lower limits at the 95% confidence level are set, excluding the stop mass below 360 to 410 GeV, depending on the higgsino mass

Search for supersymmetry in events with one lepton and multiple jets in proton-proton collisions at root s=13 TeV

Peer reviewe

Search for anomalous production of events with three or more leptons in pp collisions at √s = 8TeV

Published by the American Physical Society under the terms of the Creative Commons Attribution 3.0 License. Further distribution of this work must maintain attribution to the author(s) and the published articles title, journal citation, and DOI.A search for physics beyond the standard model in events with at least three leptons is presented. The data sample, corresponding to an integrated luminosity of 19.5fb-1 of proton-proton collisions with center-of-mass energy s=8TeV, was collected by the CMS experiment at the LHC during 2012. The data are divided into exclusive categories based on the number of leptons and their flavor, the presence or absence of an opposite-sign, same-flavor lepton pair (OSSF), the invariant mass of the OSSF pair, the presence or absence of a tagged bottom-quark jet, the number of identified hadronically decaying τ leptons, and the magnitude of the missing transverse energy and of the scalar sum of jet transverse momenta. The numbers of observed events are found to be consistent with the expected numbers from standard model processes, and limits are placed on new-physics scenarios that yield multilepton final states. In particular, scenarios that predict Higgs boson production in the context of supersymmetric decay chains are examined. We also place a 95% confidence level upper limit of 1.3% on the branching fraction for the decay of a top quark to a charm quark and a Higgs boson (t→cH), which translates to a bound on the left- and right-handed top-charm flavor-violating Higgs Yukawa couplings, λtcH and λctH, respectively, of |λtcH|2+|λctH|2<0.21

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase

Critères de Substitution à la Survie Globale dans les Essais Cliniques Randomisés en Cancérologie

In cancer randomized controlled trials (RCT), a surrogate endpoint is intended to substitute a clinically relevant endpoint, e.g. overall survival (OS), and it is supposed to predict treatment effect. Alternative endpoints, for example progression-free survival, are increasingly being used in place of OS as primary efficacy endpoints in RCTs. In practice however, the surrogate properties of these endpoints are not systematically assessed. We performed a systematic literature review to identify surrogate endpoints validated in oncology. We next conducted MAs to evaluate surrogate endpoints in two cancer settings: advanced soft-tissue sarcoma and adjuvant breast cancer. Results could not definitely validate surrogate endpoints in these indications. OS must remain the primary efficacy endpoint in these settings, even though alternative endpoints may provide valuable input in earlier phase studies (phase II trials, futility analyses). This work provides key information for the design of cancer RCTs, in particular for the choice of primary endpoints to assess treatment efficacy.Dans les essais cliniques randomisés (ECR) en cancérologie, un critère de substitution est une mesure biologique utilisée à la place d’un critère cliniquement pertinent pour le patient, par exemple la survie globale (SG), qui doit permettre de prédire l’effet attendu du traitement. Des critères alternatifs à la SG, par exemple la survie sans progression, sont de plus en plus fréquemment utilisés en tant que critère de jugement principal dans les ECR. En pratique cependant, les capacités de substitution à la SG de ces critères ne sont pas systématiquement évaluées. Nous avons dressé un état des lieux des critères de substitution validés en cancérologie à partir d’une revue systématique de la littérature. Par la suite, nous avons évalué par une approche méta-analytique des critères de substitution dans le contexte des sarcomes des tissus mous en situation avancée et du cancer du sein en situation adjuvante. Les résultats n’ont pas permis de définitivement valider de critères de substitution à la SG dans ces indications. La SG doit donc rester le critère de jugement principal des ECR, même si certains critères alternatifs restent informatifs dans des évaluations plus précoces (phase II, analyse de futilité), sous réserve que les données de survie continuent à être recueillies. Ce travail fournit des informations clés pour le développement des ECR en cancérologie afin notamment de sélectionner au mieux les critères de jugement de l’efficacité thérapeutique

Surrogate Endpoints for Overall Survival in Cancer Randomized Controlled Trials

Dans les essais cliniques randomisés (ECR) en cancérologie, un critère de substitution est une mesure biologique utilisée à la place d’un critère cliniquement pertinent pour le patient, par exemple la survie globale (SG), qui doit permettre de prédire l’effet attendu du traitement. Des critères alternatifs à la SG, par exemple la survie sans progression, sont de plus en plus fréquemment utilisés en tant que critère de jugement principal dans les ECR. En pratique cependant, les capacités de substitution à la SG de ces critères ne sont pas systématiquement évaluées. Nous avons dressé un état des lieux des critères de substitution validés en cancérologie à partir d’une revue systématique de la littérature. Par la suite, nous avons évalué par une approche méta-analytique des critères de substitution dans le contexte des sarcomes des tissus mous en situation avancée et du cancer du sein en situation adjuvante. Les résultats n’ont pas permis de définitivement valider de critères de substitution à la SG dans ces indications. La SG doit donc rester le critère de jugement principal des ECR, même si certains critères alternatifs restent informatifs dans des évaluations plus précoces (phase II, analyse de futilité), sous réserve que les données de survie continuent à être recueillies. Ce travail fournit des informations clés pour le développement des ECR en cancérologie afin notamment de sélectionner au mieux les critères de jugement de l’efficacité thérapeutique.In cancer randomized controlled trials (RCT), a surrogate endpoint is intended to substitute a clinically relevant endpoint, e.g. overall survival (OS), and it is supposed to predict treatment effect. Alternative endpoints, for example progression-free survival, are increasingly being used in place of OS as primary efficacy endpoints in RCTs. In practice however, the surrogate properties of these endpoints are not systematically assessed. We performed a systematic literature review to identify surrogate endpoints validated in oncology. We next conducted MAs to evaluate surrogate endpoints in two cancer settings: advanced soft-tissue sarcoma and adjuvant breast cancer. Results could not definitely validate surrogate endpoints in these indications. OS must remain the primary efficacy endpoint in these settings, even though alternative endpoints may provide valuable input in earlier phase studies (phase II trials, futility analyses). This work provides key information for the design of cancer RCTs, in particular for the choice of primary endpoints to assess treatment efficacy

Comparison of three longitudinal analysis models for the health-related quality of life in oncology: a simulation study

International audienceBackground: Health-Related Quality of Life (HRQoL) is an important endpoint in oncology clinical trials aiming to investigate the clinical benefit of new therapeutic strategies for the patient. However, the longitudinal analysis of HRQoL remains complex and unstandardized. There is clearly a need to propose accessible statistical methods and meaningful results for clinicians. The objective of this study was to compare three strategies for longitudinal analyses of HRQoL data in oncology clinical trials through a simulation study.Methods: The methods proposed were: the score and mixed model (SM); a survival analysis approach based on the time to HRQoL score deterioration (TTD); and the longitudinal partial credit model (LPCM). Simulations compared the methods in terms of type I error and statistical power of the test of an interaction effect between treatment arm and time. Several simulation scenarios were explored based on the EORTC HRQoL questionnaires and varying the number of patients (100, 200 or 300), items (1, 2 or 4) and response categories per item (4 or 7). Five or 10 measurement times were considered, with correlations ranging from low to high between each measure. The impact of informative missing data on these methods was also studied to reflect the reality of most clinical trials.Results: With complete data, the type I error rate was close to the expected value (5%) for all methods, while the SM method was the most powerful method, followed by LPCM. The power of TTD is low for single-item dimensions, because only four possible values exist for the score. When the number of items increases, the power of the SM approach remained stable, those of the TTD method increases while the power of LPCM remained stable. With 10 measurement times, the LPCM was less efficient. With informative missing data, the statistical power of SM and TTD tended to decrease, while that of LPCM tended to increase.Conclusions: To conclude, the SM model was the most powerful model, irrespective of the scenario considered, and the presence or not of missing data. The TTD method should be avoided for single-item dimensions of the EORTC questionnaire. While the LPCM model was more adapted to this kind of data, it was less efficient than the SM model. These results warrant validation through comparisons on real data