KRT17High/CXCL8+ tumor cells display both classical and basal features and regulate myeloid infiltration in the pancreatic cancer microenvironment.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is generally divided in two subtypes, classical and basal. Recently, single cell RNA sequencing has uncovered the co-existence of basal and classical cancer cells, as well as intermediary cancer cells, in individual tumors. The latter remains poorly understood; here, we sought to characterize them using a multimodal approach. EXPERIMENTAL DESIGN: We performed subtyping on a single cell RNA sequencing dataset containing 18 human PDAC samples to identify multiple intermediary subtypes. We generated patient-derived PDAC organoids for functional studies. We compared single cell profiling of matched blood and tumor samples to measure changes in the local and systemic immune microenvironment. We then leveraged longitudinally patient-matched blood to follow individual patients over the course of chemotherapy. RESULTS: We identified a cluster of KRT17-high intermediary cancer cells that uniquely express high levels of CXCL8 and other cytokines. The proportion of KRT17High/CXCL8+ cells in patient tumors correlated with intra-tumoral myeloid abundance, and, interestingly, high pro-tumor peripheral blood granulocytes, implicating local and systemic roles. Patient-derived organoids maintained KRT17High/CXCL8+cells and induced myeloid cell migration in an CXCL8-dependent manner. In our longitudinal studies, plasma CXCL8 decreased following chemotherapy in responsive patients, while CXCL8 persistence portended worse prognosis. CONCLUSIONS: Through single cell analysis of PDAC samples we identified KRT17High/CXCL8+ cancer cells as an intermediary subtype, marked by a unique cytokine profile and capable of influencing myeloid cells in the tumor microenvironment and systemically. The abundance of this cell population should be considered for patient stratification in precision immunotherapy.

Increase your Confidence in Opioid Prescribing: Marketing Messages in Continuing Medical Education Activities on ER/LA Opioids.

BACKGROUND: Overprescription of opioids has fueled an epidemic of addiction and overdose deaths. The FDA required manufacturers of extended-release/long-acting (ER/LA) opioids to fund continuing medical education (CME) on opioids as part of a Risk Evaluation and Mitigation Strategy (REMS). OBJECTIVES: We sought to determine whether industry-funded REMS on long-acting opioids were consistent with the FDA's goal to reduce serious, adverse outcomes resulting from inappropriate prescribing, misuse, and abuse. STUDY DESIGN: In 2018, we analyzed all internet-based REMS CME activities funded by the REMS Program Companies (RPC), a consortium of ER/LA opioid manufacturers. METHODS: We utilized systematic narrative thematic analysis, an inductive approach that allows for mapping of concepts and meanings across a body of data by identifying, recording, analyzing, and refining key narrative points, called "themes". Authors viewed all REMS activities multiple times. RESULTS: Ten themes were identified, all of which were at least somewhat incongruent with federal guidelines and their goals: 1. Chronic pain is a common, under-treated problem. 2.Chronic pain is a chronic disease.3.Opioids are an appropriate treatment for chronic pain. 4.LAs are more appropriate than immediate-release (IR) opioids for chronic pain. 5.Tolerance is normal, expected, and beneficial. 6. Opioid rotation" can maximize analgesia and minimize adverse effects.7. There is no population for whom opioids are absolutely contraindicated or inappropriate. 8. Screening and monitoring tools are effective for preventing opioid-related problems. 9. Opioid related adverse effects, such as respiratory depression and addiction, are due only to misuse and abuse. Addiction, overdose, and death are due to street drugs such as heroin and fentanyl, not prescription opioids.Themes and statements repeated in these activities were inconsistent with current medical knowledge, evidence-based federal guidelines, and FDA goals. LIMITATIONS: We evaluated only online, not live, CME. We also did not evaluate individual conflicts of interest of faculty. CONCLUSIONS: Industry-funded REMS-compliant CME on opioids contain messages that misrepresent scientific evidence and may foster overprescribing of opioids.

Multimodal Mapping of the Tumor and Peripheral Blood Immune Landscape in Human Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDA) is characterized by an immune-suppressive tumor microenvironment that renders it largely refractory to immunotherapy. We implemented a multimodal analysis approach to elucidate the immune landscape in PDA. Using a combination of CyTOF, single-cell RNA sequencing, and multiplex immunohistochemistry on patient tumors, matched blood, and non-malignant samples, we uncovered a complex network of immune-suppressive cellular interactions. These experiments revealed heterogeneous expression of immune checkpoint receptors in individual patient's T cells and increased markers of CD8+ T cell dysfunction in advanced disease stage. Tumor-infiltrating CD8+ T cells had an increased proportion of cells expressing an exhausted expression profile that included upregulation of the immune checkpoint TIGIT, a finding that we validated at the protein level. Our findings point to a profound alteration of the immune landscape of tumors, and to patient-specific immune changes that should be taken into account as combination immunotherapy becomes available for pancreatic cancer.