Improved chemosensitivity following mucolytic therapy in patient-derived models of mucinous appendix cancer.

Abundant intraperitoneal (IP) accumulation of extracellular mucus in patients with appendiceal mucinous carcinoma peritonei (MCP) causes compressive organ dysfunction and prevents delivery of chemotherapeutic drugs to cancer cells. We hypothesized that reducing extracellular mucus would decrease tumor-related symptoms and improve chemotherapeutic effect in patient-derived models of MCP. Mucolysis was achieved using a combination of bromelain (BRO) and N-acetylcysteine (NAC). Ex vivo experiments of mucolysis and chemotherapeutic drug delivery/effect were conducted with MCP and non-MCP tissue explants. In vivo experiments were performed in mouse and rat patient-derived xenograft (PDX) models of early and late (advanced) MCP. MCP tumor explants were less chemosensitive than non-MCP explants. Chronic IP administration of BRO + NAC in a mouse PDX model of early MCP and a rat PDX model of late (advanced) MCP converted solid mucinous tumors into mucinous ascites (mucolysis) that could be drained via a percutaneous catheter (rat model only), significantly reduced solid mucinous tumor growth and improved the efficacy of chemotherapeutic drugs. Combination of BRO + NAC efficiently lyses extracellular mucus in clinically relevant models of MCP. Conversion of solid mucinous tumors into mucinous ascites decreases tumor bulk and allows for minimally invasive drainage of liquified tumors. Lysis of extracellular mucus removes the protective mucinous coating surrounding cancer cells and improves chemotherapeutic drug delivery/efficacy in cancer cells. Our data provide a preclinical rationale for the clinical evaluation of BRO + NAC as a therapeutic strategy for MCP.

Subglottic Stenosis: Development of a Clinically Relevant Endoscopic Animal Model.

OBJECTIVE: Develop a clinically relevant and reproducible endoscopic animal model for subglottic stenosis amenable to testing of minimally invasive therapeutic modalities. STUDY DESIGN: Cohort study. SETTING: Division of Laboratory Animals Research, University of Pittsburgh. SUBJECTS AND METHODS: Subglottic stenosis was induced endoscopically via microsuspension laryngoscopy in 26 New Zealand white rabbits. A trimmed polypropylene brush connected to a novel electronic stenosis induction apparatus was used to create circumferential trauma to the subglottis. By using open source image analysis software, the cross-sectional areas of the stenotic and native airways were compared to calculate the percentage of stenosis and the Myer-Cotton classification grade. RESULTS: Of the 26 rabbits, 24 (92%) exhibited stenosis after the first attempt. The mean percentage of airway stenosis was 57% (range, 34%-85%; SD, 15%). Five rabbits (19.2%) died on the day of stenosis induction from procedural complications. Of the 21 rabbits, 2 demonstrated no stenosis 7 days after initial injury and so underwent reinduction of airway injury, upon which they developed stenosis. Overall, 14 of the 21 rabbits (67%) exhibited moderate to severe stenosis (grade 2 or 3). CONCLUSION: The stenosis induction apparatus reliably induced stenosis with a low mortality rate as compared with that of other methods in the literature. The device could be improved to generate a predetermined potentially reproducible grade of stenosis as desired by the operator. This method sets the stage for a clinically relevant and reproducible subglottic stenosis disease model that is amenable to testing of minimally invasive treatment modalities.