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Rationale: Cross-sectional human data suggest that enrichment of oral anaerobic bacteria in the lung is associated with an increased T-helper cell type 17 (Th17) inflammatory phenotype.Objectives: ...

In lung cancer, enrichment of the lower airway microbiota with oral commensals commonly occurs, and ex vivo models support that some of these bacteria can trigger host transcriptomic signatures associated with carcinogenesis. Here, we show that this lower airway dysbiotic signature was more prevalent in the stage IIIB–IV tumor–node–metastasis lung cancer group and is associated with poor prognosis, as shown by decreased survival among subjects with early-stage disease (I–IIIA) and worse tumor progression as measured by RECIST scores among subjects with stage IIIB–IV disease. In addition, this lower airway microbiota signature was associated with upregulation of the IL17, PI3K, MAPK, and ERK pathways in airway transcriptome, and we identified Veillonella parvula as the most abundant taxon driving this association. In a KP lung cancer model, lower airway dysbiosis with V. parvula led to decreased survival, increased tumor burden, IL17 inflammatory phenotype, and activation of checkpoint inhibitor markers. Significance: Multiple lines of investigation have shown that the gut microbiota affects host immune response to immunotherapy in cancer. Here, we support that the local airway microbiota modulates the host immune tone in lung cancer, affecting tumor progression and prognosis. See related commentary by Zitvogel and Kroemer, p. 224. This article is highlighted in the In This Issue feature, p. 211

Simulation modelling offers a great potential for modelling and analyzing business processes and, therefore, reduce the risk associated with business process change. This paper presents a study of the use of discrete event simulation to improve the operational performance of equipment rental businesses. With the purpose of reducing the turndowns due to the lack of equipment, several inventory level scenarios and maintenance management rules were tested. Simulation results show that better performance indicators are possible even without financial investment. Simulation has proved to be a powerful tool to improve the decision making by allowing to quantify the relationship between inventory levels, repair activities and turndowns.

3107 Background: Enrichment of the lower airway microbiota with oral commensals has been associated with transcriptomic changes affecting several inflammatory pathways associated with non-small cell lung cancer (NSCLC) development and progression. Using a mouse model of NSCLC, we evaluated the effects of lower airway dysbiosis on tumor progression and host transcriptomics. Methods: Preclinical model of lung cancer was constructed by introducing luminescence-tagged Kras mutated cells into C57/B6 mice, causing lung cancer to develop. Lower airway dysbiosis was induced by weekly intratracheal challenge with either PBS or Veillonella parvula in wild type and lung cancer mice. Experiments were repeated twice to evaluate for survival as well as lower airway host response using flow cytometry and RNA sequencing (HiSeq). Sequence data was processed using a validated mouse gene expression signature matrix with cibersort from https://cibersort.stanford.edu and DESeq using FDR correction. Results: In wild type mice, lower airway dysbiosis with Veillonella did not affect the survival, weight gain or airway lumen diameter. Among lung cancer mice, dysbiosis led to increased mortality, weight loss, and tumor burden. Multiple transcriptomic signatures were identified among the dysbiosis groups (both in WT and lung cancer mice). Unsupervised hierarchical clustering of immune cell profiles using cibersort on whole transcriptome showed near perfect separation between the four experimental conditions. Amongst the most differentially enriched immune cell subsets, we identified that lung dysbiosis upregulates genes annotated to Th1 and Th2 cells (p < 0.01, q < 0.2). Using flow cytometry, we identified that PD-1, IL-17, and ROR-gamma are differentially expressed in CD4+ cells in dysbiosis conditions, and these patterns are consistent in whole RNA transcriptome. Conclusions: Transcriptomic signatures reveal immune profiles associated with dysbiosis, an experimental condition associated with worse outcomes in lung cancer. This investigation provides novel insights into how disruption of the lower airway microbiome may contribute to the pathogenesis of NSCLC.

Aim: NICE trial showed that combination of chemoradiation and nimotuzumab, a humanized antibody against EGFR, is safe and appears to increase the combined complete response (cCR) rate, defined as endoscopic and/or pathologic CR, in pts with locally advanced esophageal cancer (ASCO 2014). Here we present the results of the exploratory analyses of molecular markers and their correlation to clinical outcomes. Methods: Tumor samples were obtained before chemoradiation with or without nimotuzumab. All samples were formalin-fixed and paraffin-embedded. Tumor areas were selected and macrodissected, followed by whole DNA extraction and amplification by PCR. Mutations and single nucleotide polymorphisms (SNPs) were searched in codons 12 and 13 of exon 2 for KRAS, and exons 18 to 24 for EGFR through DNA sequencing by Sangeŕs methodology. Fisher's exact test was used to compare groups. Results: Molecular analyses were performed in tumor samples from 51 of the 107 randomized patients, 18 from the control arm (chemoradiation) and 37 from the experimental arm (chemoradiation plus nimotuzumab). No mutations or SNPs were identified in KRAS among the 48 samples analyzed. Indeed, no mutations were found in EGFR, but some SNPs were identified. Except for exon 21, for all other sequenced exons at least one patient had one SNP identified, more frequently in exons 20 and 23. SNPs identified in exon 20 included 167339G > A (rs10251977) and 167339G > A (rs1050171). The latter was the most frequent detected SNP and it was identified in 11 patients (3 in the control group and 8 in the nimotuzumab group). Within each treatment arm, the cCR rates were similar between patients whose tumors harboring or not the SNP rs1050171. Although not statistically significant (P = 0.074), in the nimotuzumab group, cCR rate of tumors harboring rs1050171 was nominally higher than the rate observed for tumors without this SNP (87.5% [7/8] vs. 42.9% [6/14]). Conclusions: No mutations were found in KRAS or EGFR. Several EGFR SNPs were identified, being rs1050171 in exon 20 the most frequently found. Although exploratory, these results suggest an association between response to nimotuzumab and tumor biologic characteristics. Further exploration of this hypothesis is planned in a phase III trial. Disclosure: L.P.D.G. Neusquen: Clinical Research Department of Eurofarma S.A. All other authors have declared no conflicts of interest.

e17530 Background: Adjuvant chemotherapy is generally recommended in most patients with resected non–small cell lung cancer (NSCLC), with some restrictions according to tumor stage and size. Howeve...