Variational methods

International audienceThis contribution presents derivative-based methods for local sensitivity analysis, called Variational Sensitivity Analysis (VSA). If one defines an output called the response function, its sensitivity to inputs variations around a nominal value can be studied using derivative (gradient) information. The main issue of VSA is then to provide an efficient way of computing gradients. This contribution first presents the theoretical grounds of VSA: framework and problem statement, tangent and adjoint methods. Then it covers pratical means to compute derivatives, from naive to more sophisticated approaches, discussing their various 2 merits. Finally, applications of VSA are reviewed and some examples are presented, covering various applications fields: oceanography, glaciology, meteorology

Effect of Selumetinib vs Chemotherapy on Progression-Free Survival in Uveal Melanoma

IMPORTANCE: Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in MAPK pathway activation. OBJECTIVE: To assess the efficacy of selumetinib, a selective, non-ATP competitive inhibitor of MEK1 and MEK2, in uveal melanoma. DESIGN: Randomized open-label phase II clinical trial comparing selumetinib versus chemotherapy. Those receiving chemotherapy could receive selumetinib at the time of radiographic progression. SETTING: Fifteen academic oncology centers. PARTICIPANTS: 120 patients with metastatic uveal melanoma. INTERVENTIONS: 101 patients were randomized on a 1:1 ratio to selumetinib 75 mg orally twice daily on a continual basis (n=50) or chemotherapy (temozolomide 150 mg/m2 orally daily for 5 of every 28 days or DTIC 1000 mg/m2 intravenously every 21 days; investigator choice; n=51) until disease progression, death, intolerable toxicity, or withdrawal of consent. Following primary outcome analysis, enrollment continued in a non-randomized fashion to the superior therapy. MAIN OUTCOMES: Final analysis of progression-free survival, the primary endpoint, was assessed as of April 22, 2013. Additional endpoints, including overall survival, response rate, and safety/toxicity, were assessed as of December 31, 2013. RESULTS: Median progression-free survival for those randomized to chemotherapy and selumetinib was 7 (95% CI, 4.3 – 8.4; median treatment duration of 8 weeks (IQR, 4.3–16)) and 15.9 weeks (95% CI, 8.4 – 21.1; median treatment duration of 16.1 weeks (IQR, 8.1–25.3)), respectively (hazard ratio 0.46; 95% CI, 0.30 – 0.71; p < 0.001). Median overall survival was 9.1 (95% CI, 6.1 – 11.1) and 11.8 months (95% CI, 9.8 – 15.7) for those randomized to chemotherapy and selumetinib, respectively (hazard ratio 0.66; 95% CI, 0.41–1.06; p=0.09). No objective responses were observed with chemotherapy. 49% of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to therapy. Treatment-related adverse events were observed in 97% patients treated with selumetinib, with 37% requiring at least one dose reduction. CONCLUSIONS AND RELEVANCE: In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival and response rate; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high adverse event rate