Intestinal and tumor microbiome analysis combined with metabolomics of the anti-PD-L1 phase II PERFECT trial for resectable esophageal adenocarcinoma.

4556 Background: Both human and rodent studies provide evidence for a role of the microbiome in patients who respond to checkpoint inhibition (CI). So far, no study has unraveled the physiological link between intestinal and tumor microbiome composition in relation to response to CI. The PERFECT trial was a single-arm phase II feasibility study investigating the addition of atezolizumab (PD-L1 inhibitor) to neoadjuvant chemoradiotherapy (nCRT) for resectable esophageal adenocarcinoma (NCT03087864). An exploratory objective of this trial was to evaluate intestinal and tumor microbiome composition including plasma metabolomics as potential biomarkers for immunological and pathological response. Methods: Using 16S rRNA gene sequencing, we analyzed fecal, duodenal and tumor samples at baseline (V0), 3 weeks after start of atezolizumab (V1), and 1 week before surgery (V2). We compared microbiome composition and metabolomics from patients with pathological complete response (pCR; ypT0N0) to patients with a pathological incomplete response. Differences in alpha diversity metrics were tested using mixed linear models. Beta-diversity associations were assessed using permutational MANOVA (adonis) and multilevel PCA (mixOmics). Biomarkers were identified using a machine learning model (XGboost) feature selection. Plasma metabolomics (Metabolon) were determined with liquid chromatography mass spectrometry (LC-MS). Results: Microbiome profiles were significantly altered after start of treatment in all sample types. None of the sample types showed a relation between alpha or beta diversity and pCR. On taxonomical level, we found that the tumor and duodenal baseline samples were weak predictors for response (AUC 0.60 and 0.62, respectively), but better compared to fecal microbiome composition (AUC = 0.49). We identified the top 20 microbes that predicted pCR best in tumor and fecal samples and found significant correlations with metabolites involved in bile acid metabolism. Conclusions: Both tumor and duodenal baseline biopsies were better predictors of pathological response compared to fecal microbiome. Microbes predictive of pCR showed significant correlations with metabolites involved in bile acid metabolism, which is known to indirectly influence immunosurveillance in cancer. Data on immune response in relation to the microbiome and metabolomics are expected Spring 2020. Clinical trial information: NCT03087864 .

Paired-Associate Transfer for the A-B, C-A and the A-B, B-C Paradigms

Results of two experiments on transfer between paired-associate verbal lists, the first comparing the A-B, C-A paradigm with the A-B, C-D control and the second comparing the A-B, B-C paradigm with the A-B, C-D control are reported here. Each paradigm was represented by a separate group of 20 Ss, making a total of 80 Ss participating in both experiments. Army enlisted men averaging around the civilian mean were the nonvolunteer Ss. A low degree of List I learning was used but List II was learned to one perfect trial. Trials to successive criteria showed non-significant negative transfer in Exp. II and nonsignificant positive transfer in Exp. I. When the upper halves of Ss of known general aptitude in the two groups in Exp. I were compared, positive transfer was barely significant ( p = .05).

Relationship between Age and Recall of Meaningful Material

Older and younger Ss were equated on original learning by learning a list of words to a criterion of one perfect trial. The older and younger Ss were divided into four recall interval groups: 15 min., 1 hr., 1 day, and 1 wk. The recall interval reached significance, but neither age nor the interaction between age and recall reached an acceptable level of statistical significance.

Intrinsic Organization of Serial Lists

Twenty-four Ss learned four 12-item serial lists. One list was composed of consonants, another of numbers, another of 6 numbers followed by 6 consonants, and another of 3 numbers followed by 3 consonants followed by 3 names of months followed by 3 color names. S saw the entire list and then responded orally. The criterion was one perfect trial. By a Duncan Multiple-range F test every mean was different from each other mean ( p < .05). In another experiment 16 Ss learned 2 lists (each containing 4 categories of items). In one list the members of the categories were grouped together; in the other they were not. The mean number of trials to criterion was different by a t test ( p < .001).