Contributors NMC and LCH were responsible for study design, study coordination, cumulative data collection, data interpretation, and primary manuscript writing. WX did the statistical analyses and participated in the manuscript drafting.

Background & Aims The Atonal Homolog 1 (Atoh1 or Math1) transcription factor is required for intestinal secretory (goblet, Paneth, enteroendocrine) cell differentiation. Notch/γ-secretase inhibitors (GSIs) block proliferation and induce secretory cell differentiation in the intestine. We used genetic analyses of mice to determine whether Atoh1 mediates the effects of GSIs in normal and cancerous intestinal epithelia. Methods We studied mice with intestine-specific disruption of Atoh1 (Atoh1Δintestine), the APCmin mutation, both mutations [Atoh1Δintestine; APCmin], or littermate controls; mice were given GSI or vehicle. Colorectal cancer (CRC) cell lines were treated with GSI or vehicle and with small hairpin (sh) RNAs to reduce ATOH1. Differentiation and homeostasis was assessed by protein, RNA, and histologic analyses. Results GSIs failed to induce secretory cell differentiation or apoptosis or decrease proliferation of Atoh1-null progenitor cells, compared with wild-type cells. Exposure of APCmin adenomas to GSIs decreased proliferation and increased secretory cell numbers in an Atoh1-dependent manner. In CRC cells treated with GSI, ATOH1 levels were inversely correlated with proliferation. ATOH1 was required for secretory cell gene expression in cell lines and in mice. Conclusions ATOH1 is required for all effects of GSIs in intestinal crypts and adenomas; Notch has no unique function in intestinal progenitors and cancer cells other than to regulate ATOH1 expression. Reducing ATOH1 activity might mitigate intestinal toxicity from systemic GSI therapy for non-intestinal diseases. Among gastrointestinal malignancies, ATOH1 mediates the effects of GSIs, so ATOH1 expression levels might predict responses to these inhibitors. We propose that only the subset of CRCs that retain ATOH1 expression will respond to GSIs.

BackgroundThe neutrophil to lymphocyte ratio (NLR) is known to be prognostic for patients with advanced cancers treated with immune checkpoint inhibitors (ICI), but has generally been evaluated as a single threshold value at baseline. We evaluated NLR at baseline and within first month during treatment in patients who received ICI for advanced cancer to evaluate the prognostic value of baseline and of changes from baseline to on-treatment NLR.MethodsA retrospective review of patients with advanced cancer treated with ICI from 2011 to 2017 at the Ohio State University was performed. NLR was calculated at the initiation of ICI and repeated at median of 21 days. Overall survival (OS) was calculated from the initiation of ICI to date of death or censored at last follow-up. Significance of Cox proportional hazards models were evaluated by log-rank test. Calculations were performed using the survival and survminer packages in R, and SPSS.Results509 patients were identified and included in the analysis. Patients with baseline and on-treatment NLR < 5 had significantly longer OS (P < 0.001). The change in NLR overtime was a predictor of OS and was observed to be non-linear in nature. This property remained statistically significant with P < 0.05 after adjusting for age, body mass index, sex, cancer type, performance status, and days to repeat NLR measurement. Patients with a moderate decrease in NLR from baseline had the longest OS of 27.8 months (95% CI 21.8–33.8). Patients with significant NLR decrease had OS of 11.4 months (95% CI 6.1–16.7). Patients with a significant increase in NLR had the shortest OS of 5.0 months (95% CI 0.9–9.1).ConclusionsWe confirmed the prognostic value of NLR in patients with advanced cancer treated with ICIs. We found that change in NLR over time is a non-linear predictor of patient outcomes. Patients who had moderate decrease in NLR during treatment with ICI were found to have the longest survival, whereas a significant decrease or increase in NLR was associated with shorter survival. To our knowledge, this is the first study to demonstrate a non-linear change in NLR over time that correlates with survival.

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Background: The microbiome has been shown to affect the response to Immune Checkpoint Inhibitors (ICIs) in a small number of cancers and in preclinical models. Here, we sought to broadly survey cancers to identify those in which the microbiome may play a prognostic role using retrospective analyses of patients with advanced cancer treated with ICIs. Methods: We conducted a retrospective analysis of 690 patients who received ICI therapy for advanced cancer. We used a literature review to define a causal model for the relationship between medications, the microbiome, and ICI response to guide the abstraction of electronic health records. Medications with precedent for changes to the microbiome included antibiotics, corticosteroids, proton pump inhibitors, histamine receptor blockers, non-steroid anti-inflammatories and statins. We tested the effect of medication timing on overall survival (OS) and evaluated the robustness of medication effects in each cancer. Finally, we compared the size of the effect observed for different classes of antibiotics to taxa that have been correlated to ICI response using a literature review of culturebased antibiotic susceptibilities.