L2 Boosting on generalized Hoeffding decomposition for dependent variables. Application to Sensitivity Analysis

This paper is dedicated to the study of an estimator of the generalized Hoeffding decomposition. We build such an estimator using an empirical Gram-Schmidt approach and derive a consistency rate in a large dimensional settings. Then, we apply a greedy algorithm with these previous estimators to Sensitivity Analysis. We also establish the consistency of this $\mathbb L_2$-boosting up to sparsity assumptions on the signal to analyse. We end the paper with numerical experiments, which demonstrates the low computational cost of our method as well as its efficiency on standard benchmark of Sensitivity Analysis.Comment: 48 pages, 7 Figure

L2-Boosting for sensitivity analysis with dependent inputs

International audienceThis paper is dedicated to the study of an estimator of the generalized Hoeffding decomposition. We build such an estimator using an empirical Gram-Schmidt approach and derive a consistency rate in a large dimensional setting. We then apply a greedy algorithm with these previous estimators to a sensitivity analysis. We also establish the consistency of this L2-boosting under sparsity assumptions of the signal to be analyzed. The paper concludes with numerical experiments, that demonstrate the low computational cost of our method, as well as its efficiency on the standard benchmark of sensitivity analysis

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Prophylaxis of postoperative nausea and vomiting after cardiac surgery in high-risk patients: A randomized controlled study

Context: The role of prophylaxis for postoperative nausea and vomiting (PONV) in cardiac surgery is under debate. Aims: To study the risk factors for PONV after cardiac surgery and the role of betamethasone with or without droperidol for its prevention. Setting and Design: Randomized open-label controlled study comparing standard care with PONV prophylaxis from February to November 2016. Methods: Five hundred and two patients with planned nonemergent cardiac surgery were included. Interventions: In the intervention arm, PONV prophylaxis (4 mg betamethasone with/without 0.625 mg droperidol) was administered in high-risk patients (two or more risk factors). Patients in the control arm were treated as per routine hospital practices. Results: Female sex, past history of PONV, and migraines were associated with a significantly increased risk of PONV, while motion sickness, smoking status, and volatile anesthetics were not. Pain and treatment with nefopam or ketoprofen were associated with an increased risk of PONV. PONV was less frequent in the active arm compared to controls (45.5% vs. 54.0%, P = 0.063; visual analogic scale 10.9 vs. 15.3 mm, P = 0.043). Among the 180 patients (35.6%) with ≥2 risk factors, prophylaxis was associated with reduced PONV (intention-to-treat: 46.8% vs. 67.8%, P = 0.0061; per-protocol: 39.2% vs. 69%, P = 0.0002). In multivariate analysis, prophylaxis was independently associated with PONV (odds ratio [OR]: 0.324, 95% confidence interval: 0.167–0.629, P = 0.0009), as were female sex, past history of PONV, and migraines (OR: 3.027, 3.031, and 2.160 respectively). No drug-related side effects were reported. Conclusion: Betamethasone with/without droperidol was effective in decreasing PONV in high risk cardiac surgical patients without any side effect