Tumors are complex ecosystems composed of networks of interacting 'normal' and malignant cells. It is well recognized that cytokine-mediated cross-talk between normal stromal cells, including cancer-associated fibroblasts (CAFs), vascular endothelial cells, immune cells, and cancer cells, influences all aspects of tumor biology. Here we demonstrate that the cross-talk between CAFs and cancer cells leads to enhanced growth of oncolytic virus (OV)-based therapeutics. Transforming growth factor-β (TGF-β) produced by tumor cells reprogrammed CAFs, dampened their steady-state level of antiviral transcripts and rendered them sensitive to virus infection. In turn, CAFs produced high levels of fibroblast growth factor 2 (FGF2), initiating a signaling cascade in cancer cells that reduced retinoic acid-inducible gene I (RIG-I) expression and impeded the ability of malignant cells to detect and respond to virus. In xenografts derived from individuals with pancreatic cancer, the expression of FGF2 correlated with the susceptibility of the cancer cells to OV infection, and local application of FGF2 to resistant tumor samples sensitized them to virotherapy both in vitro and in vivo. An OV engineered to express FGF2 was safe in tumor-bearing mice, showed improved therapeutic efficacy compared to parental virus and merits consideration for clinical testing.

Background: Two reviews and an overview were produced for the Canadian Task Force on Preventive Health Care guideline on screening for esophageal adenocarcinoma in patients with chronic gastroesophageal reflux disease (GERD) without alarm symptoms. The goal was to systematically review three key questions (KQs): (1) The effectiveness of screening for these conditions; (2) How adults with chronic GERD weigh the benefits and harms of screening, and what factors contribute to their preferences and decision to undergo screening; and (3) Treatment options for Barrett's esophagus (BE), dysplasia or stage 1 EAC (overview of reviews). Methods: Bibliographic databases (e.g. Ovid MEDLINE®) were searched for each review in October 2018. We also searched for unpublished literature (e.g. relevant websites). The liberal accelerated approach was used for title and abstract screening. Two reviewers independently screened full-text articles. Data extraction and risk of bias assessments were completed by one reviewer and verified by another reviewer (KQ1 and 2). Quality assessments were completed by two reviewers independently in duplicate (KQ3). Disagreements were resolved through discussion. We used various risk of bias tools suitable for study design. The GRADE framework was used for rating the certainty of the evidence.

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Background and Study Aims: EUS-guided fine needle aspiration (EUS-FNA) is the standard in the diagnosis of pancreatic solid lesions, in particular when combined with rapid on-site evaluation of cytopathology (ROSE). More recently, a fork-tip needle for core biopsy (FNB) has been shown to be associated with excellent diagnostic yield. EUS-FNB alone; however, has not been compared to EUS-FNA+ROSE in a large clinical trial. Our aim is to compare EUS-FNB alone to EUS-FNA+ROSE in solid pancreatic lesions. Patients and Methods: Multicenter non-inferiority RCT involving 7 centers. Solid pancreatic lesions referred for EUS were considered for inclusion. The primary endpoint is diagnostic accuracy. Secondary endpoints include sensitivity/specificity, mean number of needle passes, and cost. Results: 235 patients were randomized: 115 EUS-FNB alone and 120 EUS-FNA+ROSE. Overall, 217 patients had a malignant histology. The diagnostic accuracy for malignancy of EUS-FNB alone was non-inferior to EUS-FNA+ROSE 92.2% (95% CI: 86.6-96.9%) and 93.3% (95% CI: 88.8-97.9%), respectively p=0.72. Diagnostic sensitivity for malignancy was 92.5% (95% CI: 85.7-96.7%) EUS-FNB alone vs. 96.5% (93.0-98.6%) EUS-FNA+ROSE (p=0.46) while specificity was 100% in both. Adequate histology yield was obtained in 87.5% of the EUS-FNB alone samples. Mean number of needle of passes and procedure time favored EUS-FNB alone (2.3±0.6 passes vs. 3.0±1.1 passes p≤0.01 and 19.3±8.0 minutes vs. 22.7±10.8 minutes p <0.01). EUS-FNB alone cost on average 45USD more than EUS-FNA+ROSE. Conclusion: EUS-FNB alone is non-inferior to EUS-FNA+ROSE and is associated with fewer needle passes, shorter procedure time, and excellent histological yield at comparable cost. (clinicaltrials.gov: NCT03435588).

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Recent advances in cancer therapeutics clearly demonstrate the need for innovative multiplex therapies that attack the tumour on multiple fronts. Oncolytic or “cancer-killing” viruses (OVs) represent up-and-coming multi-mechanistic immunotherapeutic drugs for the treatment of cancer. In this study, we perform an in-vitro screen based on virus-encoded artificial microRNAs (amiRNAs) and find that a unique amiRNA, herein termed amiR-4, confers a replicative advantage to the VSVΔ51 OV platform. Target validation of amiR-4 reveals ARID1A, a protein involved in chromatin remodelling, as an important player in resistance to OV replication. Virus-directed targeting of ARID1A coupled with small-molecule inhibition of the methyltransferase EZH2 leads to the synthetic lethal killing of both infected and uninfected tumour cells. The bystander killing of uninfected cells is mediated by intercellular transfer of extracellular vesicles carrying amiR-4 cargo. Altogether, our findings establish that OVs can serve as replicating vehicles for amiRNA therapeutics with the potential for combination with small molecule and immune checkpoint inhibitor therapy.

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