Search

Guanylyl cyclase C (GUCY2C) is a tumor-suppressing receptor silenced by loss of expression of the luminocrine hormones guanylin and uroguanylin early in colorectal carcinogenesis. This observation suggests oral replacement with a GUCY2C agonist may be an effective targeted chemoprevention agent. Previous studies revealed that linaclotide, an oral GUCY2C agonist formulated for gastric release, did not persist to activate guanylyl cyclase signaling in the distal rectum. Dolcanatide is an investigational oral uroguanylin analog, substituted with select D amino acids, for enhanced stability and extended persistence to activate GUCY2C in small and large intestine. However, the ability of oral dolcanatide to induce a pharmacodynamic (PD) response by activating GUCY2C in epithelial cells of the colorectum in humans remains undefined. Here, we demonstrate that administration of oral dolcanatide 27 mg daily for 7 d to healthy volunteers did not activate GUCY2C, quantified as accumulation of its product cyclic GMP, in epithelial cells of the distal rectum. These data reveal that the enhanced stability of dolcanatide, with persistence along the rostral-caudal axis of the small and large intestine, is inadequate to regulate GUCY2C across the colorectum to prevent tumorigenesis. These results highlight the importance of developing a GUCY2C agonist for cancer prevention formulated for release and activity targeted to the colorectum.

We report a 63-year-old woman who presented with 1 month of non-productive cough and non-bloody diarrhea. She was on maintenance therapy for a 15-year history of Crohn's disease. Treatment with systemic corticosteroids resulted in rapid improvement of both her diarrhea and respiratory symptoms. Our patient is unique in that she presented with tracheobronchitis during an acute flare of her Crohn's without obvious lung pathology on chest imaging. Tracheobronchitis is a rare manifestation of inflammatory bowel disease that should be considered in Crohn's disease patients presenting with persistent non-infectious cough.

Simple hepatic cysts occur in less than 5% of the population. As the technology we use for imaging advances, so does the frequency with which we identify them. Simple cysts, as presented here, do not generally require aspiration. The majority of these cysts do not require treatment, however, those larger than 4 cm are recommended for surveillance. We present two cases of simple cysts that were followed for 15 years and managed differently. The experience we acquired from these cases illustrates challenges in understanding and management and an implication that, perhaps, conservative surveillance might be best.