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

Enzyme immunoassay for the detection of group A streptococcal antigen

A competitive inhibition enzyme immunoassay for the detection of Streptococcus pyogenes directly from throat specimens or from solid bacteriological medium is described. Group A-specific polysaccharide adsorbed onto treated polystyrene beads, in conjunction with rabbit antibody to S. pyogenes, was used to determine the presence of the polysaccharide antigen. Inhibition values in excess of 65% were observed with 10(4) or more CFU of S. pyogenes per test. An inhibition of 25% was demonstrated with as few as 10(3) CFU per test. Heterologous microorganisms tested at 10(6) CFU per test reacted at levels of inhibition less than 25%. Two types of bacterial transport medium and swabs of different fiber compositions did not alter the assay performance. Accurate identification of S. pyogenes was achieved by testing single colonies picked directly from blood agar plates which had been incubated for 18 to 24 h. In addition, the assay was performed on throat specimens from children and adults having pharyngitis. A single-swab, blind study was conducted in which enzyme immunoassay reactivity was compared with results of blood agar culture and bacitracin sensitivity. When there were discordant results, serological identification was used as the confirmatory test. At an optimal cutoff value of 40% inhibition, sensitivity and specificity by enzyme immunoassay were 97.0% and 97.9%, respectively, as compared with confirmed culture results. The assay has an incubation time of 3 h and is a sensitive and specific method for the detection of S. pyogenes antigen.</jats:p

Association of the neutrophil to eosinophil ratio with response to immunotherapy-based combinations in metastatic renal cell carcinoma.

341 Background: Neutrophilia is known to be associated with worse prognosis in metastatic renal cell carcinoma (mRCC); however, less is known about the role of eosinophils in the response to immunotherapy (IO). We investigated the association of the baseline neutrophil to eosinophil ratio (NER) with outcomes to IO-based combination treatment in mRCC. Methods: Patients with mRCC treated with ipilimumab plus nivolumab, pembrolizumab plus axitinib, or avelumab plus axitinib at the Vanderbilt-Ingram Cancer Center were retrospectively identified. Patients on &gt;10mg prednisone and patients with prior IO were excluded. Baseline NER (at time of first IO) and association with progression free survival (PFS), overall survival (OS), and objective response rate (ORR) were investigated. Data cutoff was 9/1/2020. Analysis for PFS and OS was performed using the log-rank test and Mantel-Haenszel method, and analysis of the odds ratio for ORR was performed using Fischer’s exact test. Results: Sixty-one patients were identified: 89% clear cell histology, 74% prior nephrectomy, 69% IMDC intermediate risk, and 72% treatment-naïve. Patients with baseline NER &lt; median (N=31) had improved clinical outcomes compared to patients with baseline NER &gt; median (N=30) (Table). Improvement in PFS by NER was maintained when stratified by anti-PD-1/CTLA-4 and anti-PD(L)-1/VEGF (p= 0.0062 and p= 0.049); however, differences in OS and ORR were no longer significant. The median baseline NER among patients with partial response (PR) was significantly lower at 22.7 (95% CI 18.9-31.1) vs. 51.6 (95% CI 39.5-93.1) among those with progressive disease (PD) (p= 0.0054). For comparison, the median neutrophil to lymphocyte ratio was not significantly different between PR (2.60) and PD (3.84, p= 0.056). Conclusions: Patients with a low baseline NER treated with IO-based combinations had improved clinical outcomes compared to patients with a high baseline NER. Additional investigation of this parameter in larger cohorts is warranted. [Table: see text] </jats:p

Association between on-treatment eosinophil dynamics and outcomes in metastatic renal cell carcinoma patients treated with ipilimumab/nivolumab.

364 Background: Baseline neutrophil to eosinophil ratio (NER) has been associated with response to immunotherapy in metastatic renal cell carcinoma (mRCC). The association of on-treatment changes in NER and absolute eosinophil count (AEC) during induction with ipilimumab/nivolumab and relation to clinical outcomes are reported. Methods: Patients with mRCC treated with ipilimumab/nivolumab at Vanderbilt-Ingram Cancer Center were identified. Contal and O’Quigley’s method was used to determine the optimal cutpoint associated with improved progression free survival (PFS) and overall survival (OS). Multivariable Cox proportional hazard function was used to assess the association between clinical outcomes and on treatment (week 3/6/9/12) maximum AEC and lowest NER, separately. Results: 63 patients were identified: 81% clear cell histology and 79% male; 24% IMDC favorable risk, 52% intermediate risk, and 24% poor risk. When maximum AEC was coded as a continuous variable, every increase of 100 AEC was associated with improved PFS (HR: 0.89, p-value: 0.017) and OS (HR: 0.87, p-value: 0.053). When the on treatment maximum AEC was dichotomized at the optimal cutpoint of 380 cells/µL, patients with maximum AEC ≥ 380 cells/µL had longer PFS (mPFS: 11.5 months vs 2.7 months, p-value: 0.001) and OS (mOS: 29.6 months vs 16.8 months, p-value: 0.08). When on treatment lowest NER was dichotomized at the optimal cutpoint of 13.2, patients with lowest NER &lt;13.2 had improved PFS (mPFS: 12.5 months vs 2.7 months, p-value:&lt;0.001) and OS (mOS: non-reached vs 16.5 months, p-value: 0.003). After baseline characteristic adjustment (Table), higher on treatment AEC was associated with improved PFS (HR: 0.38, p-value: 0.004), and lower on treatment NER was associated with improved PFS (HR:0.34, p-value:0.002) and OS (HR: 0.38, p-value: 0.036). Conclusions: Higher AEC and low NER while on treatment are associated with improved clinical outcomes in ipilimumab/nivolumab-treated patients with mRCC. Prospective study is warranted to validate these biomarkers.[Table: see text] </jats:p